Crystallization of (20R) 19-nor-24-difluoro-1α,25-dihydroxyvitamin D3

ABSTRACT

Disclosed are methods of purifying the compound (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D 3  to obtain the compound in crystalline form. The methods typically include the steps of dissolving a product containing the compound in a solvent comprising hexane and 2-propanol, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of crystals, and recovering the crystals.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61/652,949, filed on May 30, 2012, the content of which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under DK047814 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

The field of the present invention relates to purification of organic compounds, and more particularly to the purification of the compound (20R)-19-nor-24-difluoro-1α, 25-dihydroxyvitamin D₃ (referred to herein as “24F2-DM”) by preparing the compound in crystalline form.

Purification of organic compounds, especially those designated for pharmaceutical use, is of considerable importance for chemists synthesizing such compounds. Preparation of the compound usually requires many synthetic steps and, therefore, the final product can be contaminated not only with side-products derived from the last synthetic step of the procedure but also with compounds that were formed in previous steps. Even chromatographic purification, which is a very efficient but relatively time-consuming process, does not usually provide compounds which are sufficiently pure to be used as drugs.

Depending on the method used to synthesize 1α-hydroxyvitamin D compounds, different minor undesirable compounds can accompany the final product. Thus, for example, if direct C-1 hydroxylation of the 5,6-trans geometric isomer of vitamin D is performed, followed by SeO₂/NMO oxidation and photochemical irradiation, (see Andrews et al., J. Org. Chem. 51, 1635 (1986); Calverley et al., Tetrahedron 43, 4609 (1987); Choudry et al., J. Org. Chem. 58, 1496 (1993)), the final 1α-hydroxyvitamin D product can be contaminated with 1β-hydroxy- as well as 5,6-trans isomers. If the method consists of C-1 allylic oxidation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the pre-vitamin D compound, followed by cycloreversion of the modified adduct under basic conditions, (see Nevinckx et al., Tetrahedron 47, 9419 (1991); Vanmaele et al., Tetrahedron 41, 141 (1985) and 40, 1179 (1994); Vanmaele et al., Tetrahedron Lett. 23. 995 (1982)), one can expect that the desired 1α-hydroxyvitamin can be contaminated with the pre-vitamin 5(10), 6,8-triene and 1β-hydroxy isomer. One of the most useful C-1 hydroxylation methods, of very broad scope and numerous applications, is the experimentally simple procedure elaborated by Paaren et al., J. Org. Chem. 45, 3253 (1980); and Proc. Natl. Acad. Sci. U.S.A. 75, 2080 (1978). This method consists of allylic oxidation of 3,5-cyclovitamin D derivatives, readily obtained from the buffered solvolysis of vitamin D tosylates, with SeO₂/t-BuOOH and subsequent acid-catalyzed cycloreversion to the desired 1α-hydroxy compounds. Taking into account this synthetic path it is reasonable to assume that the final product can be contaminated with the 1α-hydroxy epimer, the 5,6-trans isomer and the pre-vitamin D form. 1α-hydroxyvitamin D₄ is another undesirable contaminant found in 1α-hydroxyvitamin D compounds synthesized from vitamin D₂ or from ergosterol. 1α-hydroxyvitamin D₄ results from C-1 oxidation of vitamin D₄, which in turn is derived from contamination of the commercial ergosterol material. Typically, the final product may contain up to about 1.5% by weight 1α-hydroxyvitamin D₄. Thus, a purification technique that would eliminate or substantially reduce the amount of 1α-hydroxyvitamin D₄ in the final product to less than about 0.1-0.2% would be highly desirable.

The vitamin D conjugated triene system is not only heat- and light-sensitive but it is also prone to oxidation, leading to the complex mixture of very polar compounds. Oxidation usually happens when a vitamin D compound has been stored for a prolonged time. Other types of processes that can lead to a partial decomposition of vitamin D compounds consist of some water-elimination reactions. The driving force for these reactions is the allylic (1α-) and homoallylic (3β-) position of the hydroxy groups. The presence of such above-mentioned oxidation and elimination products can be easily detected by thin-layer chromatography.

Usually, all 1α-hydroxylatation procedures require at least one chromatographic purification. However, even chromatographically purified 1α-hydroxyvitamin D compounds, although showing consistent spectroscopic data that suggests homogeneity, do not meet the purity criteria required for therapeutic agents that can be orally, parenterally or transdermally administered. Therefore, it is evident that a suitable method of purification of the 1α-hydroxylated vitamin D compound 24F2-DM is required.

SUMMARY

Disclosed herein are methods of purifying 24F2-DM by means of crystallization to obtain 24F2-DM in crystalline form. The solvent plays an important role in the crystallization process, and is typically an individual liquid substance or a suitable mixture of different liquids. For crystallizing 24F2-DM, the most appropriate solvent and/or solvent system is characterized by the following factors:

(1) low toxicity;

(2) low boiling point;

(3) significant dependence of solubility properties with regard to temperature (condition necessary for providing satisfactory crystallization yield); and

(4) relatively low cost.

Interestingly, hexane, so frequently used for crystallization purposes, was found less suitable as the sole solvent for crystallization of 24F2-DM. However, it was found that a mixture of 2-propanol and hexane was most useful for the crystallization of 24F2-DM. In particular, it was determined that a mixture of about 10% to about 20% 2-propanol (v/v) with about 90% to about 80% hexane (v/v) (and preferably 15% 2-propanol (v/v) with about 85% hexane (v/v)) performed well. The 2-propanol/hexane solvent mixture also was easy to remove by evaporation or other well-known methods. In all cases, the crystallization process occurred easily and efficiently. The precipitated crystals were sufficiently large to assure their recovery by filtration or other means, and thus were suitable for x-ray analysis.

Accordingly, the present invention provides a compound having the formula:

in crystalline form. More specifically, the compound may be referred to as (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D₃ or “24F2-DM” in crystalline form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the three dimensional molecular structure for 24F2-DM as defined by the atomic positional parameters discovered and set forth herein.

DETAILED DESCRIPTION

Disclosed herein is the compound (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D3 (24F2-DM) in crystalline form, a pharmacologically important compound, characterized by the formula I shown below:

Also disclosed are methods of purifying 24F2-DM. The purification technique involves obtaining the 24F2-DM product in crystalline form by utilizing a crystallization procedure wherein the material to be purified is dissolved using as the solvent a mixture comprised of 2-propanol and hexane to obtain 24F2-DM. Preferably the mixture comprises from about 10% to about 20% 2-propanol and about 90% to about 80% hexane, and preferably about 15% 2-propanol and about 85% hexane (by volume). Thereafter, the solvent can be removed by evaporation, with or without vacuum, or other means as is well known, or the resultant crystals may be filtered from the mother liquor. The technique can be used to purify a wide range of final products containing 24F2-DM obtained from any known synthesis thereof, and in varying concentrations, ranging from microgram amounts to kilogram amounts. As is well known to those skilled in this art, the amount of solvent utilized may be modulated according to the amount of 24F2-DM to be purified.

EXAMPLES

The following examples are illustrative and should not be interpreted as limiting the claimed subject matter.

The usefulness and advantages of the present crystallization procedure is shown in the following specific Examples. After crystallization, the precipitated material was observed under a microscope to confirm its crystalline form. Yields of crystals were relatively high and the obtained crystals showed a relatively sharp melting point of 182-183° C. (24F2-DM).

The described crystallization process of the synthetic 24F2-DM product represents a valuable purification method, which can remove most side products derived from the synthetic path. Such impurity is the result of the contamination of starting raw materials. The crystallization process occurred easily and efficiently. The precipitated crystals were sufficiently large to assure their recovery by filtration, or other means, and thus were suitable for x-ray analysis.

Example 1 Crystallization of (20R)-19-nor-24-difluoro-1α25-dihydroxyvitamin D₃ (24F2-DM)

Crystallization from 2-Propanol/Hexane.

(20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D₃ (24F2-DM) (6 mg), was suspended in hexane (3 mL) and then 2-propanol was added dropwise to the suspension. The mixture was heated in a water bath to dissolve the vitamin, then was left at room temperature for about 1 hour, and finally was kept in a refrigerator for about 48 hours. The precipitated crystals were filtered off, washed with a small volume of a cold (0° C.) 2-propanol/hexane (3:1) mixture and dried to give crystalline material. It should be noted that an excess of 2-propanol should be avoided to get the point of saturation, (i.e., only about 1 mole or less of 2-propanol should be added).

Experimental.

A colorless prism-shaped crystal of dimensions 0.56×0.24×0.21 mm was selected for structural analysis. Intensity data were collected using a Bruker AXS Platinum 135 CCD detector controlled with the PROTEUM software suite (Bruker AXS Inc., Madison, Wis.). The x-ray source was CuKα radiation (1.54178 Å) from a Rigaku RU200 x-ray generator equipped with Montel optics, operated at 50 kV and 90 mA. The x-ray data were processed with SAINT version 7.06 A (Bruker AXS Inc.) and internally scaled with SADABS version 2005/1 (Bruker AXS Inc.). The sample was mounted in a quartz capillary and diffraction data collected at 298 K. The intensity data were measured as a series of phi and omega oscillation frames each of 1° for 30-60 sec/frame. The detector was operated in 1024×1024 mode and was positioned 5.0 cm from the sample. Cell parameters were determined from a non-linear least squares fit of 5115 peaks in the range of 3.0<theta<61.5°. The data were merged to form a set of 2949 independent data with R(int)=0.0658.

The monoclinic space group C2 was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F², (a) G. M. Sheldrick (1994), SHELXTL Version 5 Reference Manual, Bruker AXS Inc.; (b) International Tables for Crysuallography, Vol. C, Kluwer: Boston (1995). Hydrogen atom positions were determined from difference peaks and ultimately refined by a riding model with idealized geometry. Non-hydrogen atoms were refined with anisotropic displacement parameters. A total of 280 parameters were refined against 1 restraint and 2949 data to give wR2=0.1794 and S=1.027 for weights of w=1/[s²(F²)+(0.1196P)²], where P=[F_(o) ²+2F²]/3. The final R(F) was 0.0669 for the 2949 observed data. The largest shift/s.u. was 0.001 in the final refinement cycle and the final difference map had maxima and minima of 0.228 and −0.200 e/Å₃, respectively. The absolute structure was determined by refinement of the Flack parameter, H. D. Flack, Acta Cryst. A, vol. 39, 876-881 (1983).

The three dimensional structure of 24F2-DM as defined by the following physical data and atomic positional parameters described and calculated herein (Tables 1-8) is illustrated in FIG. 1.

TABLE 1 Crystal data and structure refinement for 24F2-DM. Identification code 2007 feb. 11 Empirical formula C26H42F2O3 Formula weight  440.60 Temperature 298(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group C2 Unit cell dimensions a = 23.882(5) Å α = 90° b = 6.1654(12) Å β = 121.83(3)° c = 19.632(4) Å γ = 90° Volume 2456.0(8) Å³ Z   4 Density (calculated) 1.192 Mg/m³ Absorption coefficient 0.696 mm⁻¹ F(000)  960 Crystal size 0.70 × 0.20 × 0.01 mm Theta range for data collection 2.65 to 62.79° Limiting indices −27 < h < 26, −7 < k < 5, −22 < l < 20 Reflections collected 5115 Independent reflections 2949 (R(int) = 0.0658) Completeness to Theta = 62.79 97.4% Max. and min. transmission 0.9931 and 0.6415 Refinement method Full-matrix least-squares on F² Data/restraints/parameters 2949/1/280 Goodness-of-fit on F²   1.027 Final R indices [I > 2σ(I)] R1 = 0.0669, wR2 = 0.1794 R indices (all data) R1 = 0.0812, wR2 = 0.1938 Largest diff. peak and hole 0.228 and −0.200 e⁻/Å³

TABLE 2 Atomic coordinates (Å² × 10⁴) and equivalent isotropic displacement parameters (Å² × 10³) for 24F2-DM U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) O(1) 7791(2)  7357(6) 9362(2) 65(1) O(2) 8325(2) 13611(6) 10408(2)  67(1) C(13) 9071(2) 14375(7) 6662(2) 46(1) F(2) 7592(1) 11566(8) 2797(2) 85(1) C(5) 8998(2) 11683(8) 9616(2) 51(1) F(1) 8124(2)  8914(7) 3583(2) 97(1) C(14) 8581(2) 14018(8) 6948(2) 50(1) C(3) 8802(2) 11904(8) 10755(2)  56(1) C(2) 8472(2)  9722(8) 10504(3)  58(1) O(25) 8404(2) 11739(8) 2212(2) 75(1) C(4) 9288(2)  12202(10) 10482(2)  59(1) C(8) 8875(2) 14304(8) 7829(2) 50(1) C(10) 8646(3)  9530(8) 9360(3) 60(1) C(11) 9669(3) 17024(9) 7815(2) 64(1) C(1) 8146(2)  9375(8) 9611(3) 54(1) C(7) 8823(2) 12846(8) 8292(2) 52(1) C(6) 9065(2) 13067(8) 9137(3) 54(1) C(12) 9342(2) 16680(8) 6912(2) 57(1) C(18) 9627(2) 12723(8) 7044(2) 54(1) C(15) 8230(2)  11923(10) 6537(3) 61(1) C(17) 8612(2) 13954(8) 5760(2) 52(1) C(9) 9199(3) 16504(9) 8103(3) 64(1) C(20) 8910(2) 13579(9) 5242(2) 57(1) C(27) 9084(3)  9004(14) 3081(3) 88(2) C(16) 8177(2)  12029(10) 5721(2) 64(1) C(23) 8654(2)  12262(10) 3874(3) 68(2) C(24) 8202(2)  10696(10) 3226(3) 63(1) C(25) 8401(2)  9895(10) 2645(3) 63(1) C(22) 8382(2)  12996(12) 4384(2) 71(2) C(26) 7907(3)  8192(12) 2071(3) 82(2) C(21) 9300(4)  15514(14) 5254(3) 99(2)

TABLE 3 Bond lengths [Å] for 24F2-DM. O(1)—C(1) 1.439(6) O(1)—H(1A) 0.8200 O(2)—C(3) 1.432(6) O(2)—H(2A) 0.8200 C(13)—C(18) 1.521(6) C(13)—C(17) 1.537(6) C(13)—C(12) 1.531(6) C(13)—C(14) 1.558(6) F(2)—C(24) 1.353(6) C(5)—C(6) 1.341(7) C(5)—C(4) 1.493(6) C(5)—C(10) 1.508(7) F(1)—C(24) 1.368(7) C(14)—C(8) 1.494(6) C(14)—C(15) 1.519(7) C(14)—H(14A) 0.9800 C(3)—C(2) 1.505(7) C(3)—C(4) 1.524(6) C(3)—H(3A) 0.9800 C(2)—C(1) 1.511(6) C(2)—H(2B) 0.9700 O(2)—H(2C) 0.9700 O(25)—C(25) 1.422(7) O(25)—H(25A) 0.8200 C(4)—H(4A) 0.9700 C(4)—H(4B) 0.9700 C(8)—C(7) 1.330(6) C(8)—C(9) 1.513(7) C(10)—C(1) 1.517(6) C(10)—H(10A) 0.9700 C(10)—H(10B) 0.9700 C(11)—C(9) 1.532(7) C(11)—C(12) 1.529(6) C(11)—H(11A) 0.9700 C(11)—H(11B) 0.9700 C(1)—H(1B) 0.9800 C(7)—C(6) 1.446(6) C(7)—H(7A) 0.9300 C(6)—H(6A) 0.9300 C(12)—H(12A) 0.9700 C(12)—H(12B) 0.9700 C(18)—H(18A) 0.9600 C(18)—H(18B) 0.9600 C(18)—H(18C) 0.9600 C(15)—C(16) 1.541(6) C(15)—H(15A) 0.9700 C(15)—H(15B) 0.9700 C(17)—C(20) 1.536(6) C(17)—C(16) 1.552(7) C(17)—H(17A) 0.9800 C(9)—H(9A) 0.9700 C(9)—H(9B) 0.9700 C(20)—C(21) 1.506(8) C(20)—C(22) 1.522(6) C(20)—H(20A) 0.9800 C(27)—C(25) 1.489(8) C(27)—H(27A) 0.9600 C(27)—H(27B) 0.9600 C(27)—H(27C) 0.9600 C(16)—H(16A) 0.9700 C(16)—H(16B) 0.9700 C(23)—C(24) 1.505(7) C(23)—C(22) 1.520(6) C(23)—H(23A) 0.9700 C(23)—H(23B) 0.9700 C(24)—C(25) 1.530(7) C(25)—C(26) 1.537(8) C(22)—H(22A) 0.9700 C(22)—H(22B) 0.9700 C(26)—H(26A) 0.9600 C(26)—H(26B) 0.9600 C(26)—H(26C) 0.9600 C(21)—H(21A) 0.9600 C(21)—H(21B) 0.9600 C(21)—H(21C) 0.9600

TABLE 4 Bond angles [°] for 24F2-DM. C(1)—O(1)—H(1A) 109.5 C(3)—O(2)—H(2A) 109.5 C(18)—C(13)—C(17) 111.2(4) C(18)—C(13)—C(12) 110.6(4) C(17)—C(13)—C(12) 116.8(4) C(18)—C(13)—C(14) 110.8(3) C(17)—C(13)—C(14) 100.1(3) C(12)—C(13)—C(14) 106.6(3) C(6)—C(5)—C(4) 120.5(5) C(6)—C(5)—C(10) 125.2(4) C(4)—C(5)—C(10) 114.3(4) C(8)—C(14)—C(15) 120.4(4) C(8)—C(14)—C(13) 114.5(3) C(15)—C(14)—C(13) 103.7(3) C(8)—C(14)—H(14A) 105.7 C(15)—C(14)—H(14A) 105.7 C(13)—C(14)—H(14A) 105.7 O(2)—C(3)—C(2) 110.7(3) O(2)—C(3)—C(4) 107.7(4) C(2)—C(3)—C(4) 110.9(4) O(2)—C(3)—H(3A) 109.2 C(2)—C(3)—H(3A) 109.2 C(4)—C(3)—H(3A) 109.2 C(1)—C(2)—C(3) 111.5(4) C(1)—C(2)—H(2B) 109.3 C(3)—C(2)—H(2B) 109.3 C(1)—C(2)—H(2C) 109.3 C(3)—C(2)—H(2C) 109.3 H(2B)—C(2)—H(2C) 108.0 C(25)—O(25)—H(25A) 109.5 C(5)—C(4)—C(3) 113.2(4) C(5)—C(4)—H(4A) 108.9 C(3)—C(4)—H(4A) 108.9 C(5)—C(4)—H(4B) 108.9 C(3)—C(4)—H(4B) 108.9 H(4A)—C(4)—H(4B) 107.8 C(7)—C(8)—C(14) 123.7(4) C(7)—C(8)—C(9) 125.2(4) C(14)—C(8)—C(9) 111.0(4) C(5)—C(10)—C(1) 110.0(4) C(5)—C(10)—H(10A) 109.7 C(1)—C(10)—H(10A) 109.7 C(5)—C(10)—H(10B) 109.7 C(1)—C(10)—H(10B) 109.7 H(10A)—C(10)—H(10B) 108.2 C(9)—C(11)—C(12) 111.8(4) C(9)—C(11)—H(11A) 109.3 C(12)—C(11)—H(11A) 109.3 C(9)—C(11)—H(11B) 109.2 C(12)—C(11)—H(11B) 109.3 H(11A)—C(11)—H(11B) 107.9 O(1)—C(1)—C(2) 111.6(4) O(1)—C(1)—C(10) 111.5(4) C(2)—C(1)—C(10) 110.9(4) O(1)—C(1)—H(1B) 107.5 C(2)—C(1)—H(1B) 107.5 C(10)—C(1)—H(1B) 107.5 C(8)—C(7)—C(6) 126.6(5) C(8)—C(7)—H(7A) 116.7 C(6)—C(7)—H(7A) 116.7 C(5)—C(6)—C(7) 128.4(5) C(5)—C(6)—H(6A) 115.8 C(7)—C(6)—H(6A) 115.8 C(11)—C(12)—C(13) 111.8(4) C(11)—C(12)—H(12A) 109.2 C(13)—C(12)—H(12A) 109.2 C(11)—C(12)—H(12B) 109.2 C(13)—C(12)—H(12B) 109.2 H(12A)—C(12)—H(12B) 107.9 C(13)—C(18)—H(18A) 109.5 C(13)—C(18)—H(18B) 109.5 H(18A)—C(18)—H(18B) 109.5 C(13)—C(18)—H(18C) 109.5 H(18A)—C(18)—H(18C) 109.5 H(18B)—C(18)—H(18C) 109.5 C(14)—C(15)—C(16) 103.7(4) C(14)—C(15)—H(15A) 111.0 C(16)—C(15)—H(15A) 111.0 C(14)—C(15)—H(15B) 111.0 C(16)—C(15)—H(15B) 111.0 H(15A)—C(15)—H(15B) 109.0 C(13)—C(17)—C(20) 119.4(4) C(13)—C(17)—C(16) 103.8(3) C(20)—C(17)—C(16) 112.6(4) C(13)—C(17)—H(17A) 106.8 C(20)—C(17)—H(17A) 106.8 C(16)—C(17)—H(17A) 106.8 C(8)—C(9)—C(11) 113.2(4) C(8)—C(9)—H(9A) 108.9 C(11)—C(9)—H(9B) 108.9 C(8)—C(9)—H(9B) 108.9 C(11)—C(9)—H(9B) 108.9 H(9A)—C(9)—H(9B) 107.8 C(21)—C(20)—C(22) 110.4(4) C(21)—C(20)—C(17) 111.7(4) C(22)—C(20)—C(17) 111.5(4) C(21)—C(20)—H(20A) 107.7 C(22)—C(20)—H(20A) 107.7 C(17)—C(20)—H(20A) 107.7 C(25)—C(27)—H(27A) 109.5 C(25)—C(27)—H(27B) 109.5 H(27A)—C(27)—H(27B) 109.5 C(25)—C(27)—H(27C) 109.5 H(27A)—C(27)—H(27C) 109.5 H(27B)—C(27)—H(27C) 109.5 C(15)—C(16)—C(17) 107.2(4) C(15)—C(16)—H(16A) 110.3 C(17)—C(16)—H(16A) 110.3 C(15)—C(16)—H(16B) 110.3 C(17)—C(16)—H(16B) 110.3 H(16A)—C(16)—H(16B) 108.5 C(24)—C(23)—C(22) 112.5(4) C(24)—C(23)—H(23A) 109.1 C(22)—C(23)—H(23A) 109.1 C(24)—C(23)—H(23B) 109.1 C(22)—C(23)—H(23B) 109.1 H(23A)—C(23)—H(23B) 107.8 F(2)—C(24)—F(1) 104.1(4) F(2)—C(24)—C(23) 109.2(5) F(1)—C(24)—C(23) 108.2(4) F(2)—C(24)—C(25) 108.7(3) F(1)—C(24)—C(25) 107.6(5) C(23)—C(24)—C(25) 118.1(4) O(25)—C(25)—C(27) 106.9(5) O(25)—C(25)—C(24) 106.8(5) C(27)—C(25)—C(24) 111.5(4) O(25)—C(25)—C(26) 110.6(4) C(27)—C(25)—C(26) 110.8(5) C(24)—C(25)—C(26) 110.2(4) C(23)—C(22)—C(20) 114.0(4) C(23)—C(22)—H(22A) 108.7 C(20)—C(22)—H(22A) 108.7 C(23)—C(22)—H(22B) 108.7 C(20)—C(22)—H(22B) 108.7 H(22A)—C(22)—H(22B) 107.6 C(25)—C(26)—H(26A) 109.5 C(25)—C(26)—H(26B) 109.5 H(26A)—C(26)—H(26B) 109.5 C(25)—C(26)—H(26C) 109.5 H(26A)—C(26)—H(26C) 109.5 H(26B)—C(26)—H(26C) 109.5 C(20)—C(21)—H(21A) 109.5 C(20)—C(21)—H(21B) 109.5 H(21A)—C(21)—H(21B) 109.5 C(20)—C(21)—H(21C) 109.5 H(21A)—C(21)—H(21C) 109.5 H(21B)—C(21)—H(21C) 109.5

TABLE 5 Anisotropic displacement parameters (Å² × 10³) for 24F2-DM. The anisotropic displacement factor exponent takes the form: −2π²[h²a*²U₁₁ + . . . + 2hka*b*U₁₂. U11 U22 U33 U23 U13 U12 O(1) 75 (2) 56 (2) 64 (2) 0 (2) 37 (2) −12 (2)  O(2) 85 (2) 55 (2) 82 (2) 4 (2) 57 (2)  1 (2) C(13) 53 (2) 40 (2) 49 (2) 2 (2) 30 (2)  3 (2) F(2) 60 (2) 125 (3)  63 (1) −17 (2)  28 (1)  1 (2) C(5) 55 (2) 52 (3) 58 (2) −1 (2)  37 (2) −4 (2) F(1) 127 (3)  100 (3)  91 (2) 3 (2) 75 (2) −28 (2)  C(14) 54 (2) 44 (2) 58 (2) 2 (2) 34 (2)  0 (2) C(3) 62 (2) 56 (3) 54 (2) 4 (2) 34 (2) −1 (2) C(2) 63 (2) 54 (3) 58 (2) 11 (2)  38 (2) −1 (2) O(25) 90 (2) 83 (3) 60 (2) 6 (2) 45 (2) −5 (2) C(4) 56 (2) 72 (3) 49 (2) 2 (2) 28 (2) −4 (2) C(8) 57 (2) 47 (3) 59 (2) 1 (2) 38 (2)  3 (2) C(10) 80 (3) 54 (3) 62 (2) −1 (2)  48 (2) −1 (3) C(11) 90 (3) 49 (3) 56 (2) −4 (2)  40 (2) −17 (3)  C(1) 63 (2) 45 (3) 61 (2) 8 (2) 37 (2)  0 (2) C(7) 62 (2) 50 (3) 58 (2) −2 (2)  42 (2) −3 (2) C(6) 56 (2) 52 (3) 62 (2) −1 (2)  36 (2)  0 (2) C(12) 71 (3) 42 (3) 63 (2) 0 (2) 40 (2) −9 (3) C(18) 55 (2) 53 (3) 52 (2) −1 (2)  26 (2)  3 (2) C(15) 63 (2) 66 (3) 67 (2) −6 (3)  42 (2) −12 (3)  C(17) 57 (2) 52 (3) 50 (2) 1 (2) 31 (2)  5 (2) C(9) 94 (3) 46 (3) 59 (2) −9 (2)  44 (2) −6 (3) C(20) 58 (2) 67 (3) 52 (2) −5 (2)  32 (2) −5 (2) C(27) 81 (3) 109 (6)  76 (3) 6 (4) 43 (3)  8 (4) C(16) 69 (3) 66 (3) 59 (2) −3 (3)  35 (2) −6 (3) C(23) 70 (3) 89 (4) 53 (2) −11 (3)  39 (2) −10 (3)  C(24) 61 (3) 85 (4) 46 (2) 1 (2) 30 (2) −7 (3) C(25) 64 (3) 73 (4) 55 (2) 3 (3) 33 (2) −4 (3) C(22) 66 (3) 98 (4) 49 (2) −8 (3)  31 (2) −1 (3) C(26) 95 (4) 80 (4) 75 (3) −13 (3)  48 (3) −19 (3)  C(21) 122 (5)  124 (6)  75 (3) −26 (4)  68 (3) −49 (5) 

TABLE 6 Hydrogen coordinates (Å² × 10⁴) and isotropic displacement parameters (Å² × 10³) for 24F2-DM. x y z U(eq) H(1A) 7993 6436 9709 98 H(2A) 8012 13327 10455 101 H(14A) 8249 15164 6691 60 H(3A) 9039 12019 11341 67 H(2B) 8797 8593 10787 66 H(2C) 8143 9613 10650 66 H(25A) 8055 11798 1779 113 H(4A) 9440 13693 10577 71 H(4B) 9667 11276 10802 71 H(10A) 8964 8360 9604 73 H(10B) 8424 9384 8782 73 H(11A) 10056 16104 8096 77 H(11B) 9813 18520 7945 77 H(1B) 7826 10546 9341 65 H(7A) 8610 11555 8049 62 H(6A) 9297 14334 9379 65 H(12A) 9661 16953 6760 68 H(12B) 8984 17711 6630 68 H(18A) 9923 12972 6860 82 H(18B) 9447 11287 6895 82 H(18C) 9862 12868 7616 82 H(15A) 7797 11855 6468 73 H(15B) 8484 10670 6843 73 H(17A) 8321 15218 5536 63 H(9A) 9443 16555 8684 77 H(9B) 8860 17610 7905 77 H(20A) 9214 12348 5470 69 H(27A) 9385 10090 3436 132 H(27B) 9202 8588 2702 132 H(27C) 9104 7759 3387 132 H(16A) 7722 12257 5293 76 H(16B) 8331 10685 5618 76 H(23A) 8721 13521 3629 81 H(23B) 9079 11576 4216 81 H(22A) 8110 11847 4395 85 H(22B) 8102 14250 4132 123 H(26A) 7472 8808 1788 123 H(26B) 7913 6956 2373 123 H(26C) 8025 7751 1695 123 H(21A) 9629 15868 5799 148 H(21B) 9010 16728 5007 148 H(21C) 9511 15179 4964 148

TABLE 7 Torsion angles [deg] for 24F2-DM. C(18)—C(13)—C(14)—C(8) 62.4(5) C(17)—C(13)—C(14)—C(8) 179.8(4) C(12)—C(13)—C(14)—C(8) −58.1(5) C(18)—C(13)—C(14)—C(15) −70.8(4) C(17)—C(13)—C(14)—C(15) 46.7(4) C(12)—C(13)—C(14)—C(15) 168.7(4) O(2)—C(3)—C(2)—C(1) 64.7(5) C(4)—C(3)—C(2)—C(1) −54.8(5) C(6)—C(5)—C(4)—C(3) 130.9(5) C(10)—C(5)—C(4)—C(3) −49.6(6) O(2)—C(3)—C(4)—C(5) −71.4(5) C(2)—C(3)—C(4)—C(5) 49.9(6) C(15)—C(14)—C(8)—C(7) −3.6(7) C(13)—C(14)—C(8)—C(7) −128.4(5) C(15)—C(14)—C(8)—C(9) 179.7(4) C(13)—C(14)—C(8)—C(9) 54.9(5) C(6)—C(5)—C(10)—C(1) −128.4(5) C(4)—C(5)—C(10)—C(1) 52.1(5) C(3)—C(2)—C(1)—O(1) −175.9(4) C(3)—C(2)—C(1)—C(10) 59.1(6) C(5)—C(10)—C(1)—O(1) 178.8(3) C(5)—C(10)—C(1)—C(2) −56.1(5) C(14)—C(8)—C(7)—C(6) −176.5(4) C(9)—C(8)—C(7)—C(6) −0.3(7) C(4)—C(5)—C(6)—C(7) 179.8(4) C(10)—C(5)—C(6)—C(7) 0.3(8) C(8)—C(7)—C(6)—C(5) 176.8(5) C(9)—C(11)—C(12)—C(13) −56.0(6) C(18)—C(13)—C(12)—C(11) −63.4(5) C(17)—C(13)—C(12)—C(11) 168.1(4) C(14)—C(13)—C(12)—C(11) 57.2(5) C(8)—C(14)—C(15)—C(16) −164.9(4) C(13)—C(14)—C(15)—C(16) −35.2(5) C(18)—C(13)—C(17)—C(20) −48.2(6) C(12)—C(13)—C(17)—C(20) 80.1(5) C(14)—C(13)—C(17)—C(20) −165.3(4) C(18)—C(13)—C(17)—C(16) 78.2(4) C(12)—C(13)—C(17)—C(16) −153.6(4) C(14)—C(13)—C(17)—C(16) −39.0(4) C(7)—C(8)—C(9)—C(11) 133.5(5) C(14)—C(8)—C(9)—C(11) −49.9(5) C(12)—C(11)—C(9)—C(8) 51.1(6) C(13)—C(17)—C(20)—C(21) −61.0(6) C(16)—C(17)—C(20)—C(21) 177.0(4) C(13)—C(17)—C(20)—C(22) 175.0(5) C(16)—C(17)—C(20)—C(22) 53.0(6) C(14)—C(15)—C(16)—C(17) 10.4(5) C(13)—C(17)—C(16)—C(15) 18.5(5) C(20)—C(17)—C(16)—C(15) 149.0(4) C(22)—C(23)—C(24)—F(2) 52.8(6) C(22)—C(23)—C(24)—F(1) −60.0(6) C(22)—C(23)—C(24)—C(25) 177.5(5) F(2)—C(24)—C(25)—O(25) 61.0(5) F(1)—C(24)—O(25)—O(25) 173.2(4) C(23)—C(24)—C(25)—O(25) −64.0(5) F(2)—C(24)—C(25)—C(27) 177.4(5) F(1)—C(24)—C(25)—C(27) −70.4(6) C(23)—C(24)—C(25)—C(27) 52.4(7) F(2)—C(24)—C(25)—C(26) −59.1(6) F(1)—C(24)—C(25)—C(26) 53.1(5) C(23)—C(24)—C(25)—C(26) 175.9(5) C(24)—C(23)—C(22)—C(20) 150.8(5) C(21)—C(20)—C(22)—C(23) 64.3(7) C(17)—C(20)—C(22)—C(23) −170.9(5)

TABLE 8 Observed and calculated structure factors for 24F2-DM. h k l 10Fc 10Fc 10s 1 −7 0 41 42 4 3 −7 0 38 34 6 0 −6 0 53 41 8 2 −6 0 43 53 10 4 −6 0 11 27 10 6 −6 0 63 68 4 10 −6 0 0 31 1 1 −5 0 65 57 6 3 −5 0 310 315 8 5 −5 0 131 133 8 7 −5 0 143 185 7 9 −5 0 23 18 23 11 −5 0 36 47 8 13 −5 0 91 67 10 15 −5 0 82 62 10 0 −4 0 683 673 48 2 −4 0 87 87 4 4 −4 0 282 277 6 6 −4 0 31 27 8 8 −4 0 0 13 1 10 −4 0 59 60 8 12 −4 0 81 99 10 14 −4 0 14 30 14 16 −4 0 64 55 5 18 −4 0 55 51 16 1 −3 0 313 323 15 3 −3 0 73 82 5 7 −3 0 185 179 6 9 −3 0 258 262 7 11 −3 0 211 177 6 13 −3 0 88 89 6 15 −3 0 55 68 7 17 −3 0 78 92 5 19 −3 0 71 65 6 21 −3 0 28 28 8 0 −2 0 1114 1129 40 2 −2 0 208 206 13 4 −2 0 795 756 34 6 −2 0 512 529 28 8 −2 0 210 179 11 10 −2 0 246 231 8 12 −2 0 174 177 6 14 −2 0 85 84 5 16 −2 0 87 99 7 18 −2 0 41 48 14 20 −2 0 114 102 8 22 −2 0 31 33 14 1 −1 0 1222 1167 35 3 −1 0 1786 1655 83 5 −1 0 1028 1026 42 7 −1 0 657 823 39 9 −1 0 202 252 11 11 −1 0 128 136 10 13 −1 0 46 36 12 15 −1 0 225 216 7 17 −1 0 149 139 5 19 −1 0 41 51 17 21 −1 0 42 40 14 2 0 0 866 876 44 4 0 0 2245 2228 115 6 0 0 185 242 10 8 0 0 305 354 16 10 0 0 38 24 21 12 0 0 306 301 11 14 0 0 213 215 6 16 0 0 62 62 15 18 0 0 0 5 1 20 0 0 27 30 26 1 1 0 1218 1167 63 3 1 0 1655 1656 94 5 1 0 989 1026 55 9 1 0 210 231 11 11 1 0 138 136 11 13 1 0 35 36 29 15 1 0 219 216 11 17 1 0 126 140 10 19 1 0 39 51 32 21 1 0 53 41 16 2 2 0 224 209 11 4 2 0 758 755 41 6 2 0 550 532 26 8 2 0 204 180 12 10 2 0 242 328 14 12 2 0 183 176 13 14 2 0 91 84 12 16 2 0 89 99 12 18 2 0 44 47 25 −6 2 2 749 742 35 −4 2 2 169 161 9 −2 2 2 211 214 9 0 2 2 489 463 25 2 2 2 576 530 25 4 2 2 467 442 24 6 2 2 234 218 13 8 2 2 170 152 13 10 2 2 142 130 7 12 2 2 209 212 13 14 2 2 104 96 10 16 2 2 100 107 10 20 2 2 49 49 15 −21 3 2 18 33 18 −19 3 2 178 160 12 −17 3 2 65 59 17 −15 3 2 153 162 10 −13 3 2 101 125 12 9 3 2 189 167 11 11 3 2 93 78 11 13 3 2 0 30 1 15 3 2 41 64 35 19 3 2 43 35 20 16 4 2 41 37 26 −3 −7 3 41 44 4 −1 −7 3 20 15 20 −12 −6 3 44 44 6 −10 −6 3 34 29 9 −8 −6 3 30 19 11 −6 −6 3 57 59 5 −4 −6 3 84 79 4 −2 −6 3 80 81 4 0 −6 3 70 69 4 2 −6 3 19 13 18 4 −6 3 25 28 24 6 −6 3 0 18 1 8 −6 3 0 15 1 −17 −5 3 28 24 10 −15 −5 3 39 35 9 −13 −5 3 50 64 7 −11 −5 3 66 72 20 −9 −5 3 87 82 7 −7 −5 3 288 270 8 −5 −5 3 155 129 9 −3 −5 3 106 88 7 −1 −5 3 156 154 5 1 −5 3 153 160 6 3 −5 3 162 160 6 5 −5 3 75 69 10 7 −5 3 78 93 10 9 −5 3 1 48 1 11 −5 3 27 8 27 13 −5 3 22 9 22 −20 −4 3 35 23 10 −18 −4 3 0 24 1 −16 −4 3 59 75 13 −14 −4 3 103 134 12 −12 −4 3 33 32 14 −10 −4 3 83 82 5 −8 −4 3 140 136 4 −6 −4 3 104 102 3 −4 −4 3 470 447 9 −2 −4 3 140 128 3 0 −4 3 329 319 8 2 −4 3 83 78 4 4 −4 3 209 203 6 6 −4 3 209 203 9 8 −4 3 139 143 9 10 −4 3 111 120 10 12 −4 3 0 46 1 14 −4 3 28 21 27 16 −4 3 27 40 27 −21 −3 3 53 52 8 −19 −3 3 66 60 7 −17 −3 3 54 12 16 −15 −3 3 95 92 5 −13 −3 3 51 62 7 −11 −3 3 73 77 6 −9 −3 3 3 329 7 −7 −3 3 191 185 11 −5 −3 3 213 213 12 −3 −3 3 169 199 10 −1 −3 3 309 290 16 1 −3 3 155 167 11 3 −3 3 258 237 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−11 −3 8 144 145 5 −9 −3 8 225 220 5 −7 −3 8 178 180 5 −25 −1 10 0 26 1 −23 −1 10 113 107 16 −21 −1 10 79 77 8 −19 −1 10 150 163 7 −17 −1 10 94 100 5 −15 −1 10 278 271 7 −13 −1 10 405 423 9 −11 −1 10 284 298 16 −9 −1 10 282 278 16 −3 −1 10 238 249 15 −1 −1 10 112 94 4 1 −1 10 318 308 8 3 −1 10 239 236 10 5 −1 10 49 60 9 7 −1 10 217 242 9 9 −1 10 55 71 8 11 −1 10 93 103 7 13 −1 10 30 29 15 −26 0 10 54 28 15 −24 0 10 39 29 26 −22 0 10 134 156 9 −20 0 10 151 132 10 −18 0 10 73 74 14 −16 0 10 33 46 31 −14 0 10 45 66 11 −8 0 10 672 620 35 −6 0 10 391 499 20 −4 0 10 147 167 10 −2 0 10 459 449 24 0 0 10 226 214 8 2 0 10 220 244 5 4 0 10 94 87 4 6 0 10 140 133 5 8 0 10 55 64 7 10 0 10 88 81 8 12 0 10 86 83 7 14 0 10 32 28 14 −27 1 10 32 28 31 −25 1 10 0 27 1 −23 1 10 114 107 10 −21 1 10 77 77 14 −19 1 10 176 163 11 −17 1 10 105 101 10 −15 1 10 249 270 15 −11 1 10 287 299 16 −9 1 10 297 278 15 −7 1 10 220 210 13 −5 1 10 332 301 18 −3 1 10 277 250 13 −1 1 10 109 94 5 1 1 10 305 308 9 3 1 10 237 236 8 5 1 10 51 58 11 7 1 10 201 242 12 9 1 10 81 71 8 11 1 10 119 103 5 −26 2 10 91 68 9 −24 2 10 63 56 15 −22 2 10 30 45 30 −6 2 10 281 250 14 −4 2 10 152 144 8 −2 2 10 86 81 11 0 2 10 175 173 6 2 2 10 156 157 6 4 2 10 111 110 7 6 2 10 58 60 9 8 2 10 42 34 12 10 2 10 114 105 17 12 2 10 0 25 1 −5 3 10 147 173 13 −3 3 10 158 163 12 −1 3 10 110 95 8 1 3 10 257 237 13 3 3 10 371 377 12 5 3 10 96 100 7 7 3 10 252 263 11 9 3 10 103 93 12 11 3 10 121 88 13 0 4 10 143 141 10 2 4 10 184 173 10 4 4 10 33 45 33 6 4 10 44 43 20 8 4 10 85 78 6 −10 −6 11 85 75 5 −6 −6 11 59 67 9 −4 −6 11 76 73 8 −17 −6 11 0 20 1 −11 −1 13 141 156 4 −9 −1 13 291 293 7 −7 −1 13 140 129 5 −5 −1 13 118 114 4 −3 −1 13 114 109 5 −1 −1 13 162 161 6 1 −1 13 126 122 7 3 −1 13 113 122 6 5 −1 13 74 89 7 7 −1 13 132 136 7 9 −1 13 0 25 1 −26 0 13 111 100 10 −24 0 13 104 88 7 −22 0 13 78 67 8 −20 0 13 70 76 10 −18 0 13 5 7 5 −16 0 13 29 40 29 −14 0 13 342 363 14 −12 0 13 431 434 14 −10 0 13 362 375 13 −8 0 13 158 155 6 −6 0 13 296 272 7 −4 0 13 47 48 7 −2 0 13 461 431 12 0 0 13 91 82 7 2 0 13 17 26 17 4 0 13 57 50 7 6 0 13 34 7 17 8 0 13 170 144 8 10 0 13 57 43 7 −25 1 13 83 82 11 −23 1 13 100 89 10 −21 1 13 83 90 11 −19 1 13 124 124 9 −17 1 13 242 247 14 −15 1 13 169 189 13 −13 1 13 41 39 30 −11 1 13 142 156 14 −9 1 13 291 292 10 −7 1 13 141 129 7 −5 1 13 117 115 5 −3 1 13 97 107 7 −1 1 13 171 163 7 1 1 13 129 123 14 3 1 13 116 121 8 5 1 13 91 89 11 7 1 13 149 136 8 −14 2 13 66 87 15 −12 2 13 286 283 16 −10 2 13 138 141 10 −8 2 13 113 123 9 −6 2 13 242 232 11 −4 2 13 112 122 6 −2 2 13 195 186 8 0 2 13 104 85 6 2 2 13 48 54 10 4 2 13 43 46 11 6 2 13 155 146 13 8 2 13 61 54 6 −9 3 13 75 80 12 −7 3 13 291 279 15 −5 3 13 153 159 11 −1 3 13 110 103 6 1 3 13 90 81 6 3 3 13 0 25 1 5 3 13 87 80 6 7 3 13 43 42 12 −4 4 13 51 41 17 −2 4 13 34 54 33 0 4 13 95 85 8 2 4 13 71 70 10 4 4 13 35 3 35 −15 −5 14 150 136 6 −13 −5 14 170 139 6 −11 −5 14 143 124 7 −9 −5 14 30 36 29 −7 −5 14 58 64 13 −5 −5 14 63 57 11 −1 −5 14 3 24 3 −20 −4 14 36 16 22 −18 −4 14 74 76 6 −16 −4 14 156 143 7 −14 −4 14 76 99 11 −12 −4 14 200 198 19 −10 −4 14 23 20 22 −8 −4 14 125 138 5 −6 −4 14 104 104 5 −13 −3 17 88 77 7 −11 −3 17 93 92 6 −9 −3 17 93 97 6 −7 −3 17 45 62 8 −5 −3 17 107 101 6 −24 −2 17 23 20 22 −22 −2 17 15 23 14 −20 −2 17 92 92 5 −18 −2 17 179 186 8 −16 −2 17 96 93 5 −14 −2 17 126 115 6 −12 −2 17 88 88 8 −10 −2 17 153 154 8 −8 −2 17 214 217 9 −6 −2 17 97 101 6 −4 −2 17 81 86 6 −2 −2 17 18 29 17 0 −2 17 19 25 19 −25 1 17 31 49 16 −23 1 17 47 43 10 −21 1 17 127 137 5 −19 1 17 67 81 6 −17 1 17 112 136 5 −15 1 17 25 25 24 −13 1 17 43 42 12 −11 1 17 187 169 9 −9 1 17 190 169 5 −5 1 17 49 34 10 −3 1 17 28 37 27 −1 1 17 65 61 8 1 1 17 48 44 10 3 1 17 91 80 6 −24 0 17 78 67 7 −22 0 17 28 1 28 −20 0 17 55 57 10 −18 0 17 30 19 29 −16 0 17 236 284 12 −14 0 17 210 197 11 −12 0 17 517 573 17 −10 0 17 109 126 6 −8 0 17 137 154 11 −6 0 17 47 49 9 −4 0 17 0 18 1 −2 0 17 108 109 5 0 0 17 14 1 13 2 0 17 12 20 12 4 0 17 60 58 7 −25 1 17 53 49 13 −23 1 17 52 42 17 −21 1 17 125 136 9 −19 1 17 68 82 12 −17 1 17 121 136 6 −15 1 17 32 26 31 −13 1 17 31 41 30 −11 1 17 182 169 12 −9 1 17 159 169 14 −7 1 17 111 130 6 −5 1 17 32 33 24 −3 1 17 18 36 17 −1 1 17 65 62 8 1 1 17 33 43 32 −20 2 17 75 93 12 −18 2 17 190 186 10 −16 2 17 91 92 12 −14 2 17 103 113 11 −12 2 17 80 89 9 −10 2 17 144 155 23 −8 2 17 199 217 16 20 2 0 121 101 9 3 0 194 176 15 13 3 0 82 87 13 15 3 0 68 61 17 17 3 0 80 92 14 −3 −7 1 69 70 3 −1 −7 1 13 28 13 1 −7 1 55 50 3 −8 −6 1 48 49 5 −6 −6 1 57 66 15 −4 −6 1 24 25 14 −2 −6 1 57 53 5 0 −6 1 103 101 4 2 −6 1 110 132 6 4 −6 1 205 208 6 8 −6 1 86 92 8 10 −6 1 84 81 8 −17 −5 1 50 52 14 −15 −5 1 72 47 11 −13 −5 1 43 42 12 −11 −5 1 11 31 10 −9 −5 1 90 122 5 −7 −5 1 84 95 6 −5 −5 1 92 112 6 −3 −5 1 343 329 10 −1 −5 1 28 31 16 1 −5 1 160 164 6 3 −5 1 96 93 5 5 −5 1 163 168 20 7 −5 1 37 30 7 9 −5 1 25 29 25 11 −5 1 10 27 10 13 −5 1 41 41 24 15 −5 1 16 28 16 −18 −4 1 50 46 6 −16 −4 1 75 86 14 −14 −4 1 61 67 9 −12 −4 1 46 50 15 −10 −4 1 137 129 6 −8 −4 1 50 46 8 −6 −4 1 138 131 4 −4 −4 1 137 125 3 −2 −4 1 221 211 4 0 −4 1 210 196 5 2 −4 1 155 132 5 4 −4 1 101 91 6 6 −4 1 250 247 7 8 −4 1 150 142 5 10 −4 1 34 51 33 12 −4 1 144 163 5 14 −4 1 67 64 5 16 −4 1 66 74 14 18 −4 1 33 19 33 −21 −3 1 33 22 12 −19 −3 1 78 81 7 −17 −3 1 59 63 9 −15 −3 1 31 42 27 −13 −3 1 49 35 23 −11 −3 1 106 101 4 −9 −3 1 108 108 4 −7 −3 1 499 448 25 −5 −3 1 752 678 38 −3 −3 1 301 295 18 −1 −3 1 424 447 16 1 −3 1 457 428 30 3 −3 1 394 438 21 7 −3 1 116 98 6 9 −3 1 271 270 7 11 −3 1 72 54 5 13 −3 1 112 129 18 15 −3 1 150 157 22 17 −3 1 70 71 15 19 −3 1 47 56 7 −22 −2 1 50 71 7 −20 −2 1 127 106 7 −18 −2 1 36 43 18 −16 −2 1 141 132 6 −14 −2 1 77 83 8 −12 −2 1 134 135 5 −10 −2 1 263 250 12 −8 −2 1 258 209 13 −6 −2 1 351 372 19 −4 −2 1 287 302 12 −2 −2 1 361 353 19 0 −2 1 225 229 8 2 −2 1 366 330 19 8 −2 1 343 330 18 9 −3 3 163 160 6 11 −3 3 250 287 8 13 −3 3 218 244 9 15 −3 3 89 93 5 17 −3 3 42 43 8 −22 −2 3 72 74 8 −20 −2 3 63 42 10 −18 −2 3 147 148 7 −16 −2 3 76 74 7 −14 −2 3 177 174 5 −12 −2 3 186 176 6 −10 −2 3 222 187 12 −8 −2 3 696 768 36 −6 −2 3 160 167 9 −4 −2 3 368 415 21 −2 −2 3 32 31 9 0 −2 3 406 375 21 2 −2 3 497 479 26 8 −2 3 333 350 14 10 −2 3 142 150 6 12 −2 3 131 124 7 14 −2 3 155 168 8 16 −2 3 164 189 8 18 −2 3 92 98 6 20 −2 3 45 43 7 −21 −1 3 70 74 17 −19 −1 3 221 209 7 −17 −1 3 81 81 7 −15 −1 3 157 160 6 −13 −1 3 474 478 18 −11 −1 3 218 255 14 −9 −1 3 304 304 16 −7 −1 3 151 177 9 −5 −1 3 458 481 25 −3 −1 3 636 628 30 −1 −1 3 1352 1275 47 1 −1 3 453 427 23 3 −1 3 360 364 18 5 −1 3 146 137 6 7 −1 3 188 192 11 9 −1 3 85 72 10 11 −1 3 217 221 7 13 −1 3 256 254 18 15 −1 3 35 23 24 17 −1 3 127 118 8 19 −1 3 36 36 17 −24 0 3 54 55 11 −22 0 3 277 230 14 −20 0 3 85 92 10 −18 0 3 154 172 10 −16 0 3 24 31 24 −14 0 3 158 162 7 −12 0 3 267 218 15 −10 0 3 161 161 11 −8 0 3 1323 1304 68 −6 0 3 715 675 37 −4 0 3 1082 1021 39 −2 0 3 413 433 15 0 0 3 1456 1433 86 2 0 3 685 671 35 4 0 3 393 493 20 6 0 3 67 68 8 8 0 3 91 101 9 10 0 3 72 70 7 12 0 3 230 232 6 14 0 3 208 204 7 16 0 3 58 45 12 18 0 3 54 60 12 20 0 3 39 60 15 −23 1 3 149 126 11 −21 1 3 61 75 13 −19 1 3 194 210 13 −17 1 3 80 60 11 −15 1 3 161 159 7 −13 1 3 463 478 25 −11 1 3 257 257 12 −9 1 3 312 301 16 −5 1 3 482 482 17 −3 1 3 607 628 22 −1 1 3 1313 1274 70 1 1 3 454 425 23 3 1 3 365 365 19 5 1 3 132 139 10 7 1 3 196 192 11 9 1 3 82 72 13 11 1 3 219 227 8 13 1 3 249 254 11 −5 1 5 131 141 6 −3 1 5 185 183 10 −1 1 5 945 915 50 3 1 5 646 629 33 5 1 5 147 153 10 7 1 5 383 390 16 9 1 5 202 199 8 11 1 5 125 121 7 17 1 5 50 71 6 −24 2 5 47 50 21 −22 2 5 69 61 15 −20 2 5 126 133 12 −18 2 5 356 342 18 −16 2 5 262 263 14 −14 2 5 348 398 20 −4 2 5 489 472 23 −2 2 5 432 419 23 0 2 5 297 275 16 2 2 5 492 480 27 4 2 5 386 364 20 6 2 5 192 199 8 8 2 5 27 31 26 16 2 5 93 90 10 18 2 5 87 79 8 −23 3 5 9 51 9 −21 3 5 45 64 28 −19 3 5 211 190 11 5 3 5 197 194 12 11 3 5 86 91 12 13 3 5 37 27 36 15 3 5 48 36 20 17 3 5 19 19 19 8 4 5 83 81 11 10 4 5 43 46 28 12 4 5 29 42 29 14 4 5 23 23 23 −14 −6 6 46 62 8 −12 −6 6 68 64 5 −10 −6 6 40 41 9 −8 −6 6 17 12 17 −6 −6 6 121 118 5 −4 −6 6 106 102 4 0 −6 6 35 41 20 2 −6 6 71 72 9 4 −6 6 33 28 26 6 −6 6 34 32 20 −19 −5 6 49 42 7 −17 −5 6 99 102 5 −15 −5 6 143 132 12 −13 −5 6 151 148 6 −11 −5 6 82 94 8 −9 −5 6 34 38 15 −7 −5 6 132 132 6 −5 −5 6 179 173 7 −3 −5 6 106 93 5 −1 −5 6 167 167 6 1 −5 6 115 129 8 3 −5 6 126 136 8 5 −5 6 65 91 11 7 −5 6 4 29 3 9 −5 6 0 39 1 11 −5 6 0 14 1 −22 −4 6 43 35 7 −20 −4 6 61 61 7 −18 −4 6 55 66 7 −16 −4 6 188 198 6 −14 −4 6 59 61 8 −12 −4 6 362 354 8 −10 −4 6 209 193 5 −8 −4 6 368 368 7 −6 −4 6 57 58 4 −4 −4 6 269 248 6 −2 −4 6 243 228 7 0 −4 6 255 227 7 2 −4 6 33 19 32 4 −4 6 198 185 12 6 −4 6 149 161 11 8 −4 6 19 12 18 10 −4 6 6 19 5 12 −4 6 27 22 27 −23 −3 6 96 92 5 −21 −3 6 131 119 6 −19 −3 6 27 33 26 −17 −3 6 244 221 7 −15 −3 6 188 174 5 −13 −3 6 241 239 5 −11 −3 6 196 198 4 −5 −3 8 335 316 9 −3 −3 8 156 163 5 −1 −3 8 296 270 8 1 −3 8 128 131 10 3 −3 8 231 223 12 5 −3 8 171 162 11 7 −3 8 4 19 3 −24 −2 8 101 101 10 −22 −2 8 134 115 13 −20 −2 8 352 327 12 −18 −2 8 390 372 11 −16 −2 8 325 326 8 −14 −2 8 302 296 7 −12 −2 8 165 162 5 −10 −2 8 382 351 20 −8 −2 8 410 387 21 −6 −2 8 320 283 16 −4 −2 8 166 145 11 −2 −2 8 215 198 13 2 −2 8 226 235 10 4 −2 8 226 232 9 6 −2 8 328 307 12 8 −2 8 174 172 8 10 −2 8 55 60 6 12 −2 8 73 91 6 14 −2 8 15 7 15 −25 −1 8 77 70 10 −23 −1 8 36 34 35 −21 −1 8 16 24 16 −19 −1 8 102 89 7 −17 −1 8 222 220 9 −15 −1 8 225 235 7 −13 −1 8 417 397 22 −11 −1 8 315 282 17 −9 −1 8 1151 1082 60 −7 −1 8 210 216 12 −5 −1 8 140 152 10 −3 −1 8 618 660 32 −1 −1 8 642 598 34 1 −1 8 188 203 11 3 −1 8 187 200 8 5 −1 8 104 96 6 7 −1 8 234 236 10 9 −1 8 155 143 8 11 −1 8 155 165 8 13 −1 8 82 85 7 15 −1 8 40 43 11 −26 0 8 47 33 17 −24 0 8 43 54 21 −22 0 8 61 68 14 −20 0 8 18 50 18 −18 0 8 0 13 1 −16 0 8 233 238 7 −14 0 8 659 627 34 −12 0 8 75 81 14 −10 0 8 120 111 11 −8 0 8 419 407 15 −6 0 8 180 190 7 −4 0 8 30 15 29 −2 0 8 188 184 11 0 0 8 1184 1393 61 2 0 8 206 195 12 4 0 8 550 544 12 6 0 8 0 8 1 8 0 8 46 41 8 10 0 8 0 19 1 12 0 8 64 54 9 14 0 8 73 78 7 16 0 8 0 14 1 −25 1 8 53 70 11 −23 1 8 20 54 20 −21 1 8 16 24 16 −19 1 8 109 88 11 −17 1 8 240 219 12 −15 1 8 229 236 12 −9 1 8 1168 1081 59 −7 1 8 219 215 12 −5 1 8 151 158 10 −3 1 8 659 658 31 −1 1 8 669 598 33 1 1 8 210 204 11 3 1 8 182 199 7 5 1 8 108 97 6 7 1 8 224 237 10 9 1 8 143 141 11 11 1 8 165 164 20 13 1 8 107 86 10 −15 −5 11 22 23 22 −13 −5 11 60 45 16 −11 −5 11 46 33 10 −9 −5 11 5 8 5 −7 −5 11 197 202 7 −5 −5 11 81 85 9 −3 −5 11 136 152 9 −1 −5 11 85 77 9 1 −5 11 15 30 14 3 −5 11 65 49 10 −22 −4 11 35 37 29 −20 −4 11 41 34 40 −18 −4 11 0 12 1 −16 −4 11 100 97 4 −14 −4 11 83 83 5 −12 −4 11 35 91 17 −10 −4 11 109 110 10 −8 −4 11 161 189 10 −6 −4 11 108 123 5 −4 −4 11 252 249 8 −2 −4 11 129 121 9 0 −4 11 197 191 12 2 −4 11 67 58 12 4 −4 11 94 102 10 6 −4 11 18 33 17 −23 −3 11 18 8 18 −21 −3 11 11 15 10 −19 −3 11 81 81 6 −17 −3 11 124 150 6 −15 −3 11 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−16 0 11 106 120 6 −14 0 11 205 227 6 −12 0 11 119 108 8 −4 −4 14 80 87 11 −2 −4 14 129 117 9 0 −4 14 61 67 12 2 −4 14 0 32 1 −23 −3 14 48 38 9 −21 −3 14 123 107 5 −19 −3 14 9 30 9 −17 −3 14 221 251 8 −15 −3 14 62 68 7 −13 −3 14 96 97 12 −11 −3 14 280 268 9 −9 −3 14 181 174 24 −7 −3 14 109 109 10 −5 −3 14 256 251 14 −3 −3 14 212 224 7 −26 −2 14 46 19 16 −24 −2 14 61 53 7 −22 −2 14 22 35 21 −20 −2 14 116 134 5 −18 −2 14 161 162 7 −16 −2 14 110 119 7 −14 −2 14 273 260 7 −12 −2 14 244 229 6 −10 −2 14 92 82 4 −8 −2 14 338 342 9 −6 −2 14 204 194 9 −4 −2 14 337 382 16 −2 −2 14 130 141 6 0 −2 14 119 127 7 2 −2 14 41 51 9 4 −2 14 77 71 6 −27 −1 14 37 25 22 −25 −1 14 68 62 8 −23 −1 14 35 57 17 −21 −1 14 48 60 10 −19 −1 14 96 93 6 −17 −1 14 84 95 6 −15 −1 14 130 127 5 −13 −1 14 159 150 5 −11 −1 14 115 112 4 −9 −1 14 229 217 6 −7 −1 14 114 115 4 −5 −1 14 188 188 6 −3 −1 14 34 21 11 −1 −1 14 45 42 11 1 −1 14 23 34 22 3 −1 14 30 36 17 5 −1 14 65 80 7 7 −1 14 68 58 7 9 −1 14 48 37 6 −26 −1 14 40 39 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−19 −1 1 58 59 8 −17 −1 1 66 68 8 −15 −1 1 66 74 6 −13 −1 1 93 95 5 −11 −1 1 727 708 37 −9 −1 1 342 398 18 −7 −1 1 436 450 16 −5 −1 1 1157 1181 41 −3 −1 1 1214 1185 47 −1 −1 1 773 738 21 3 −1 1 556 514 19 5 −1 1 602 581 30 7 −1 1 149 182 9 9 −1 1 197 196 11 11 −1 1 289 283 9 13 −1 1 143 142 6 15 −1 1 98 97 6 17 −1 1 78 88 9 19 −1 1 117 92 7 21 −1 1 44 47 12 −22 0 1 70 67 10 −20 0 1 75 56 11 −18 0 1 0 50 1 −16 0 1 65 74 11 −14 0 1 68 53 9 −12 0 1 52 67 21 −10 0 1 460 501 24 −8 0 1 114 127 9 −6 0 1 486 469 25 −4 0 1 1594 1546 32 −2 0 1 314 326 16 0 0 1 229 229 8 2 0 1 495 493 25 4 0 1 1308 1448 67 6 0 1 94 111 7 8 0 1 218 255 12 10 0 1 132 149 9 12 0 1 203 207 8 14 0 1 200 204 6 16 0 1 128 121 6 18 0 1 99 91 10 −21 1 1 77 46 12 −19 1 1 65 58 13 −17 1 1 53 68 19 −15 1 1 80 73 10 −13 1 1 106 94 12 −11 1 1 726 709 37 −7 1 1 457 447 22 −5 1 1 1142 1182 59 −3 1 1 1172 1188 43 −1 1 1 736 735 28 1 1 1 2044 1952 105 3 1 1 540 517 29 5 1 1 582 584 31 7 1 1 166 182 9 9 1 1 209 197 11 11 1 1 293 283 10 13 1 1 160 141 7 15 1 1 87 96 11 17 1 1 78 88 11 19 1 1 92 91 11 −22 2 1 99 77 9 −20 2 1 98 106 11 −18 2 1 40 43 37 −16 2 1 141 131 10 −14 2 1 90 82 11 −12 2 1 131 136 9 −10 2 1 237 250 15 −8 2 1 236 209 14 −6 2 1 378 371 18 −4 2 1 305 301 14 −2 2 1 365 353 18 0 2 1 240 231 12 2 2 1 371 331 19 4 2 1 258 257 14 6 2 1 1148 1115 59 8 2 1 351 830 18 10 2 1 444 449 15 12 2 1 213 220 10 15 1 3 0 23 1 19 1 3 56 36 12 −24 2 3 31 50 31 −22 2 3 91 74 11 −20 2 3 61 43 16 −18 2 3 153 148 10 −16 2 3 79 74 15 −14 2 3 171 176 12 −4 2 3 408 415 19 −2 2 3 33 33 23 0 2 3 400 377 21 2 2 3 500 477 26 4 2 3 961 390 49 6 2 3 530 505 27 8 2 3 333 531 12 10 2 3 156 150 8 12 2 3 129 125 15 14 2 3 154 167 10 20 2 3 56 43 10 −21 3 3 63 52 15 −19 3 3 35 61 34 −17 3 3 0 12 1 −15 3 3 76 92 15 7 3 3 252 250 14 9 3 3 168 160 12 11 3 3 243 236 14 17 3 3 53 43 17 19 3 3 0 11 1 10 4 3 123 120 9 12 4 3 41 46 92 14 4 3 0 20 1 16 4 3 29 40 29 −14 −6 4 20 21 17 −12 −6 4 55 58 7 −10 −6 4 56 46 5 −8 −6 4 35 38 10 −6 −6 4 96 95 4 −4 −6 4 37 30 7 −2 −6 4 54 51 4 0 −6 4 59 53 4 2 −6 4 157 144 9 4 −6 4 47 52 13 6 −6 4 33 32 27 8 −6 4 44 49 13 −17 −5 4 35 42 9 −15 −5 4 39 54 17 −13 −5 4 51 57 8 −11 −5 4 120 256 8 −9 −5 4 125 212 7 −7 −5 4 44 37 9 −5 −5 4 55 52 7 −3 −5 4 204 189 14 −1 −5 4 137 127 4 1 −5 4 83 75 4 3 −5 4 89 99 9 5 −5 4 30 38 29 7 −5 4 45 50 16 9 −5 4 34 28 33 11 −5 4 20 17 20 13 −5 4 17 11 17 −20 −4 4 58 51 12 −18 −4 4 51 54 8 −16 −4 4 58 58 7 −14 −4 4 98 104 6 −12 −4 4 38 49 11 −10 −4 4 163 158 5 −8 −4 4 232 225 5 −6 −4 4 187 192 4 −4 −4 4 146 129 4 −2 −4 4 150 144 4 0 −4 4 80 77 4 2 −4 4 85 73 8 4 −4 4 158 143 7 6 −4 4 0 16 1 8 −4 4 73 59 12 10 −4 4 78 95 12 12 −4 4 37 31 37 14 −4 4 25 14 25 −23 −3 4 40 34 10 −21 −3 4 66 59 6 −19 −3 4 36 22 15 −17 −3 4 169 269 10 −15 −3 4 233 223 7 −13 −3 4 333 349 8 −11 −3 4 102 112 4 −9 −3 4 167 169 4 −7 −3 4 181 169 11 −9 −3 6 93 91 3 −7 −3 6 292 283 8 −5 −3 6 308 270 16 −3 −3 6 86 54 12 −1 −3 6 144 134 7 1 −3 6 52 65 12 3 −3 6 147 226 7 5 −3 6 260 271 13 7 −3 6 192 179 11 9 −3 6 115 114 10 −24 −2 6 38 18 16 −22 −2 6 58 60 9 −20 −2 6 108 208 5 −18 −2 6 84 84 5 −16 −2 6 61 61 6 −14 −2 6 310 324 6 −12 −2 6 234 244 7 −10 −2 6 52 38 19 −8 −2 6 243 225 13 −6 −2 6 304 520 16 −4 −2 6 502 502 27 −2 −2 6 433 368 22 0 −2 6 301 267 17 2 −2 6 287 258 16 6 −2 6 94 81 5 8 −2 6 112 119 7 10 −2 6 165 166 8 12 −2 6 28 23 16 14 −2 6 50 52 7 16 −2 6 15 35 15 −23 −1 6 119 117 8 −21 −1 6 87 65 10 −19 −1 6 99 93 7 −17 −1 6 121 121 6 −15 −1 6 235 239 7 −13 −1 6 90 88 14 −11 −1 6 245 219 13 −9 −1 6 0 13 1 −7 −1 6 353 345 16 −5 −1 6 645 606 23 −3 −1 6 493 472 18 −1 −1 6 581 572 19 1 −1 6 488 464 17 3 −1 6 483 519 25 5 −1 6 157 158 10 7 −1 6 149 159 5 9 −1 6 191 184 6 11 −1 6 112 106 7 13 −1 6 151 149 8 15 −1 6 45 44 12 17 −1 6 40 17 11 −26 0 6 11 17 10 −24 0 6 0 3 1 −22 0 6 61 66 13 −20 0 6 92 110 10 −18 0 6 55 34 15 −16 0 6 42 67 24 −14 0 6 17 19 16 −12 0 6 573 520 30 −10 0 6 1062 977 54 −8 0 6 1553 1406 80 −6 0 6 592 550 21 −4 0 6 276 283 10 −2 0 6 85 103 5 0 0 6 205 181 8 2 0 6 615 731 31 4 0 6 99 105 9 6 0 6 184 162 11 8 0 6 86 86 6 10 0 6 88 91 10 12 0 6 102 99 5 14 0 6 160 149 6 16 0 6 134 119 9 18 0 6 25 16 25 −25 1 6 0 13 1 −23 1 6 100 116 10 −21 1 6 92 85 11 −19 1 6 102 93 12 −17 1 6 123 119 10 −15 1 6 249 138 12 −13 1 6 88 89 14 −11 1 6 236 220 14 −9 1 6 24 11 24 −7 1 6 344 345 13 −5 1 6 655 606 33 −3 1 6 523 473 25 −1 1 6 513 572 31 15 1 8 43 43 12 −24 2 8 99 100 11 −22 2 8 99 114 15 −20 2 8 370 327 17 −18 2 8 395 372 19 −6 2 8 302 282 17 −4 2 8 166 145 12 −2 2 8 215 197 13 0 2 8 253 238 15 2 2 8 238 235 9 4 2 8 216 231 7 6 2 8 308 308 9 8 2 8 173 272 7 10 2 8 52 60 10 12 2 8 84 91 7 14 2 8 17 7 17 −23 3 8 34 19 33 −1 3 8 275 269 15 1 3 8 135 131 9 3 3 8 223 224 12 5 3 8 159 161 12 7 3 8 32 17 31 9 3 8 45 50 14 11 3 8 152 147 8 13 3 8 0 19 1 4 4 8 159 162 11 6 4 8 109 108 9 8 4 8 51 38 17 10 4 8 75 45 20 12 4 8 45 18 25 −12 −6 9 0 25 1 −10 −6 9 78 92 7 −8 −6 9 56 55 6 −4 −6 9 92 91 7 −2 −6 9 30 23 29 0 −6 9 35 32 19 2 −6 9 26 33 25 −19 −5 9 18 19 18 −17 −5 9 0 15 1 −15 −5 9 0 25 1 −13 −5 9 23 41 22 −11 −5 9 137 132 5 −9 −5 9 138 142 6 −7 −5 9 60 64 13 −5 −5 9 114 125 5 −3 −5 9 200 232 11 −1 −5 9 49 45 13 1 −5 9 62 80 10 3 −5 9 70 57 10 5 −5 9 78 72 9 7 −5 9 30 29 30 −22 −4 9 38 31 15 −20 −4 9 29 42 21 −18 −4 9 64 68 7 −16 −4 9 220 206 7 −14 −4 9 204 197 5 −12 −4 9 165 167 6 −10 −4 9 108 94 6 −8 −4 9 73 65 7 −6 −4 9 79 74 6 −4 −4 9 0 16 1 −2 −4 9 93 76 10 0 −4 9 92 95 10 2 −4 9 133 141 9 4 −4 9 93 96 10 6 −4 9 0 21 1 8 −4 9 64 72 13 10 −4 9 60 55 12 −23 −3 9 46 40 14 −21 −3 9 61 63 7 −19 −3 9 112 119 10 −17 −3 9 88 79 6 −15 −3 9 92 96 10 −13 −3 9 58 87 8 −11 −3 9 44 48 8 −9 −3 9 165 158 5 −7 −3 9 225 222 6 −5 −3 9 234 234 7 −3 −3 9 116 114 5 −1 −3 9 377 362 11 1 −3 9 303 293 15 3 −3 9 378 364 18 5 −3 9 191 206 13 −24 −2 9 46 50 19 −22 −2 9 41 30 17 −20 −2 9 234 226 7 −18 −2 9 132 124 5 −10 0 11 36 46 36 −8 0 11 402 406 21 −6 0 11 227 226 13 −4 0 11 656 677 34 −2 0 11 66 80 5 0 0 11 332 331 7 2 0 11 116 119 4 4 0 11 42 43 8 6 0 11 113 108 5 8 0 11 8 11 8 10 0 11 31 27 21 12 0 11 48 27 9 −27 1 11 0 9 1 −25 1 11 38 56 37 −23 1 11 2 48 2 −21 1 11 101 100 11 −19 1 11 64 64 15 −17 1 11 203 218 8 −15 1 11 40 48 25 −13 1 11 256 260 14 −11 1 11 83 90 8 −9 1 11 414 386 20 −7 1 11 329 312 17 −5 1 11 102 89 6 −3 1 11 131 140 6 −1 1 11 95 92 6 1 1 11 31 41 18 3 1 11 107 106 6 5 1 11 76 77 7 7 1 11 0 13 1 9 1 11 78 72 6 11 1 11 125 107 7 −24 2 11 109 87 9 −22 2 11 65 58 14 −12 2 11 38 52 29 −10 2 11 160 172 12 −8 2 11 228 246 13 −6 2 11 133 130 7 −4 2 11 272 288 8 −2 2 11 170 174 7 0 2 11 86 74 11 2 2 11 94 96 10 4 2 11 288 298 15 6 2 11 44 24 11 8 2 11 131 131 12 10 2 11 30 25 22 12 2 11 29 13 28 −7 3 11 166 160 12 −5 3 11 264 280 15 −3 3 11 245 235 13 −1 3 11 248 227 12 1 3 11 144 113 10 3 3 11 39 40 17 5 3 11 137 147 16 7 3 11 108 91 12 9 3 11 72 55 9 −2 4 11 135 122 9 0 4 11 209 190 11 2 4 11 65 58 12 4 4 11 113 102 8 6 4 11 44 32 16 8 4 11 63 47 7 −17 −5 12 26 39 26 −15 −5 12 65 39 11 −13 −5 12 43 48 11 −11 −5 12 113 99 8 −9 −5 12 74 70 7 −7 −5 12 122 116 5 −5 −5 12 56 58 12 −3 −5 12 91 79 9 −1 −5 12 89 81 9 1 −5 12 54 45 11 3 −5 12 42 49 14 −20 −4 12 0 17 1 −18 −4 12 154 134 9 −16 −4 12 48 43 9 −14 −4 12 202 200 13 −12 −4 12 115 144 9 −10 −4 12 122 136 13 −8 −4 12 33 43 15 −6 −4 12 23 36 22 −4 −4 12 54 66 16 −2 −4 12 49 58 17 0 −4 12 93 88 10 2 −4 12 82 84 10 4 −4 12 50 48 14 −23 −3 12 28 30 21 −10 2 14 98 82 9 −8 2 14 341 341 11 −6 2 14 206 194 8 −4 2 14 366 382 12 −2 2 14 101 141 8 0 2 14 122 128 6 2 2 14 44 51 10 4 2 14 73 71 8 6 2 14 0 14 1 −11 3 14 279 267 14 −9 3 14 198 174 11 −7 3 14 105 109 9 −5 3 14 266 251 13 −3 3 14 233 223 8 −1 3 14 40 49 15 1 3 14 71 66 15 3 3 14 47 37 11 5 3 14 0 25 1 −6 4 14 92 104 10 −4 4 14 82 88 10 −2 4 14 115 117 9 0 4 14 74 67 9 2 4 14 36 32 14 −15 −5 15 105 94 7 −13 −5 15 66 62 5 −11 −5 15 173 149 6 −9 −5 15 5 13 5 −7 −5 15 25 35 24 −5 −5 15 54 52 11 −20 −4 15 36 36 20 −18 −4 15 0 22 1 −16 −4 15 68 48 7 −14 −4 15 108 100 8 −12 −4 15 0 10 1 −10 −4 15 114 114 6 −8 −4 15 151 143 10 −6 −4 15 95 92 10 −4 −4 15 65 42 12 −2 −4 15 0 5 1 0 −4 15 46 48 15 −23 −3 15 41 29 10 −21 −3 15 108 99 5 −19 −3 15 69 83 6 −17 −3 15 189 182 10 −15 −3 15 274 264 8 −13 −3 15 168 155 7 −11 −3 15 299 273 10 −9 −3 15 119 115 14 −7 −3 15 135 128 23 −5 −3 15 66 78 6 −3 −3 15 32 28 15 −24 −2 15 102 96 6 −22 −2 15 15 12 14 −20 −2 15 198 215 6 −18 −2 15 58 56 8 −16 −2 15 184 181 11 −14 −2 15 211 190 6 −12 −2 15 137 133 4 −10 −2 15 114 122 4 −8 −2 15 130 126 8 −6 −2 15 252 272 11 −4 −2 15 177 194 9 −2 −2 15 173 188 8 0 −2 15 117 127 6 2 −2 15 57 61 7 4 −2 15 54 39 6 −25 −1 15 44 33 11 −23 −1 15 46 48 11 −21 −1 15 104 210 5 −19 −1 15 12 17 12 −17 −1 15 142 149 11 −15 −1 15 152 158 11 −13 −1 15 143 128 15 −11 −1 15 384 355 10 −9 −1 15 267 242 7 −7 −1 15 338 316 9 −5 −1 15 130 120 6 −3 −1 15 208 197 9 −1 −1 15 60 57 8 1 −1 15 164 164 9 3 −1 15 45 51 9 5 −1 15 45 37 10 7 −1 15 64 47 6 −26 0 15 111 88 6 −24 0 15 104 93 7 −22 0 15 66 66 10 −20 0 15 46 53 11 2 0 18 78 81 6 −21 1 18 102 108 20 −19 1 18 6 17 5 −17 1 18 101 125 7 −15 1 18 134 135 16 −13 1 18 173 204 8 −11 1 18 151 160 8 −9 1 18 82 87 8 −7 1 18 132 139 11 −5 1 18 58 67 12 −3 1 18 47 36 11 −1 1 18 68 61 10 −20 2 18 40 42 29 −18 2 18 0 23 1 −16 2 18 34 45 99 −14 2 18 97 104 7 −12 2 18 66 67 25 −10 2 18 87 96 7 −8 2 18 39 46 16 −6 2 18 131 136 15 −4 2 18 46 43 13 −2 2 18 81 76 6 0 2 18 61 50 6 −17 3 18 44 46 22 −15 3 18 119 122 10 −13 3 18 15 27 15 −11 3 18 158 138 10 −9 3 18 79 78 8 −7 3 18 81 86 7 −5 3 18 21 27 21 −3 4 18 47 44 9 −12 4 18 79 79 10 −10 4 18 40 50 24 −8 4 18 32 31 32 −19 −3 19 29 37 28 −17 −3 19 85 83 5 −15 −3 19 32 44 17 −13 −3 19 16 24 16 −11 −3 19 28 27 27 −9 −3 19 125 105 6 −7 −2 19 64 66 5 −22 −2 19 24 37 24 −20 −2 19 41 49 10 −18 −2 19 77 64 11 −16 −2 19 44 48 27 −14 −2 19 56 43 11 −12 −2 19 37 20 19 −10 −2 19 60 63 9 −8 −2 19 57 61 9 −6 −2 19 48 52 10 −4 −2 19 92 76 6 −2 −2 19 62 64 5 −23 −1 19 132 114 5 −21 −1 19 51 38 8 −19 −1 19 138 123 7 −17 −1 19 105 104 15 −15 −1 19 0 27 1 −13 −1 19 62 58 6 −11 −1 19 56 68 7 −9 −1 19 133 117 8 −7 −1 19 15 24 15 −5 −1 19 71 57 8 −3 −1 19 42 34 12 −1 −1 19 114 101 6 −24 0 19 124 100 14 −22 0 19 186 164 11 −20 0 19 55 62 10 −18 0 19 64 63 8 14 2 1 62 68 14 16 2 1 104 110 11 18 2 1 41 51 26 −19 3 1 100 61 19 −17 3 1 54 63 21 −15 3 1 0 41 1 −13 3 1 0 34 1 9 3 1 255 271 14 11 3 1 50 54 22 13 3 1 134 128 9 15 3 1 161 157 10 17 3 1 64 71 17 4 1 60 19 12 −3 −7 2 61 59 3 −1 −7 2 80 75 3 1 −7 2 85 86 5 −10 −6 2 73 74 5 −8 −6 2 49 54 6 −6 −6 2 63 56 10 −4 −6 2 14 8 14 −2 −6 2 90 100 10 0 −6 2 56 64 12 2 −6 2 128 133 5 4 −6 2 174 172 8 6 −6 2 140 131 9 8 −6 2 55 63 11 10 −6 2 0 39 1 −17 −5 2 10 12 10 −15 −5 2 11 12 11 −13 −5 2 117 115 18 −11 −5 2 70 82 13 −9 −5 2 51 52 10 −7 −5 2 96 114 6 −5 −5 2 96 107 4 −3 −5 2 188 158 9 −1 −5 2 301 293 11 1 −5 2 416 410 10 3 −5 2 174 167 4 5 −5 2 252 248 6 7 −5 2 32 15 32 9 −5 2 63 74 11 11 −5 2 0 19 1 13 −5 2 0 21 1 15 −5 2 56 47 11 −20 −4 2 40 22 9 −18 −4 2 63 65 6 −16 −4 2 104 119 5 −14 −4 2 119 149 7 −12 −4 2 156 178 7 −10 −4 2 254 249 8 −8 −4 2 54 61 6 −6 −4 2 373 359 7 −4 −4 2 51 47 7 −2 −4 2 281 271 6 0 −4 2 151 135 5 2 −4 2 183 173 4 4 −4 2 153 142 5 6 −4 2 12 7 11 8 −4 2 59 60 5 10 −4 2 149 160 5 12 −4 2 174 162 7 14 −4 2 128 119 10 16 −4 2 32 37 32 −21 −3 2 22 33 21 −19 −3 2 175 161 7 −17 −3 2 59 60 13 −15 −3 2 139 161 9 −13 −3 2 129 125 5 −11 −3 2 128 109 5 −9 −3 2 123 119 4 −7 −3 2 194 164 11 −5 −3 2 581 537 30 −3 −3 2 394 441 20 −1 −3 2 435 392 22 1 −3 2 279 288 15 3 −3 2 797 694 41 5 −3 2 328 309 18 7 −3 2 150 141 6 9 −3 2 173 166 7 11 −3 2 76 78 6 13 −3 2 22 31 22 15 −3 2 61 65 14 17 −3 2 35 25 12 19 −3 2 44 34 6 −22 −2 2 42 43 13 −20 −2 2 42 34 15 −18 −2 2 88 90 8 −5 −3 4 522 507 21 −3 −3 4 259 276 14 −1 −3 4 158 143 11 1 −3 4 184 159 12 3 −3 4 202 201 9 5 −3 4 178 174 8 7 −3 4 301 285 15 9 −3 4 242 240 8 11 −3 4 52 56 7 13 −3 4 35 17 10 15 −3 4 104 98 6 −24 −2 4 19 23 18 −22 −2 4 29 31 28 −20 −2 4 229 215 8 −18 −2 4 298 273 8 −16 −2 4 175 177 6 −14 −2 4 162 172 5 −12 −2 4 210 209 1 −10 −2 4 112 124 10 −8 −2 4 61 56 11 −6 −2 4 414 453 21 −4 −2 4 104 120 9 −2 −2 4 260 262 9 0 −2 4 212 196 12 2 −2 4 230 219 13 4 −2 4 593 539 30 8 −2 4 107 98 7 10 −2 4 34 42 14 12 −2 4 72 65 7 14 −2 4 100 118 6 16 −2 4 0 15 1 18 −2 4 66 63 6 −21 −1 4 69 53 12 −19 −1 4 237 210 11 −17 −1 4 125 123 5 −15 −1 4 176 185 5 −13 −1 4 461 465 22 −11 −1 4 147 146 11 −9 −1 4 184 192 12 −7 −1 4 287 317 17 −5 −1 4 181 185 10 −3 −1 4 676 659 23 −1 −1 4 694 679 25 1 −1 4 454 408 24 3 −1 4 527 521 18 5 −1 4 226 222 11 7 −1 4 237 240 13 9 −1 4 71 76 5 11 −1 4 145 148 6 13 −1 4 236 217 11 15 −1 4 216 184 10 17 −1 4 228 129 8 19 −1 4 163 147 8 −24 0 4 153 123 10 −22 0 4 157 127 11 −20 0 4 0 17 1 −18 0 4 171 162 12 −16 0 4 5 21 5 −14 0 4 0 34 1 −12 0 4 64 55 18 −10 0 4 194 179 12 −6 0 4 241 221 13 −4 0 4 145 118 6 −2 0 4 298 297 13 0 0 4 698 710 25 2 0 4 358 394 28 4 0 4 318 377 16 6 0 4 324 382 17 8 0 4 130 127 10 10 0 4 257 263 7 12 0 4 172 175 6 14 0 4 101 101 8 16 0 4 148 121 9 18 0 4 196 176 9 20 0 4 47 56 10 −25 1 4 77 78 9 −23 1 4 61 42 14 −21 1 4 48 53 20 −19 1 4 209 210 14 −17 1 4 129 124 20 −15 1 4 176 134 8 −13 1 4 428 456 24 −11 1 4 170 146 10 −9 1 4 213 192 11 −7 1 4 323 318 16 −5 1 4 178 185 7 −3 1 4 650 663 35 1 1 6 486 463 25 3 1 6 491 520 25 5 1 6 180 160 10 7 1 6 164 160 10 9 1 6 178 183 13 13 1 6 147 149 10 15 1 6 42 43 12 17 1 6 46 16 13 −24 2 6 7 18 7 −22 2 6 61 60 17 −20 2 6 126 108 10 −18 2 6 70 64 16 −16 2 6 0 61 1 −4 2 6 529 501 26 −2 2 6 428 366 22 0 2 6 313 269 16 2 2 6 296 259 16 4 2 6 164 161 12 6 2 6 89 80 14 8 2 6 103 120 15 12 2 6 0 23 1 14 2 6 50 52 14 16 2 6 30 36 30 −23 3 6 84 92 11 −21 3 6 129 118 10 −19 3 6 57 33 19 3 3 6 131 126 10 5 3 6 253 270 13 7 3 6 168 180 12 9 3 6 114 114 10 11 3 6 10 51 10 13 3 6 13 26 13 15 3 6 0 8 1 6 4 6 144 150 11 8 4 6 0 12 1 10 4 6 0 19 1 10 4 6 29 22 28 14 4 6 9 12 9 −14 −6 7 42 59 10 −12 −6 7 20 7 20 −10 −6 7 58 61 6 −8 −6 7 59 67 13 −6 −6 7 83 76 11 −4 −6 7 154 141 7 −2 −6 7 43 47 14 0 −6 7 42 26 14 2 −6 7 36 38 19 4 −6 7 45 41 13 −17 −5 7 80 94 5 −15 −5 7 81 85 6 −13 −5 7 66 70 7 −11 −5 7 180 163 6 −9 −5 7 0 16 1 −7 −5 7 78 80 5 −5 −5 7 44 53 7 −3 −5 7 52 47 15 −1 −5 7 26 46 26 1 −5 7 73 82 9 3 −5 7 74 97 9 5 −5 7 71 96 10 7 −5 7 19 35 18 9 −5 7 33 39 32 −22 −4 7 111 104 5 −20 −4 7 24 24 23 −18 −4 7 72 84 6 −16 −4 7 67 59 7 −14 −4 7 210 216 11 −12 −4 7 169 159 5 −10 −4 7 205 192 4 −8 −4 7 93 96 5 −6 −4 7 185 178 6 −4 −4 7 197 189 6 −2 −4 7 190 183 9 0 −4 7 186 191 12 2 −4 7 222 221 17 4 −4 7 174 187 11 6 −4 7 106 94 10 8 −4 7 100 101 10 10 −4 7 58 68 15 12 −4 7 37 4 29 −23 −3 7 50 44 8 −21 −3 7 161 150 6 −19 −3 7 231 222 11 −17 −3 7 194 195 6 −15 −3 7 465 447 10 −13 −3 7 210 225 5 −11 −3 7 102 101 3 −16 −2 9 78 85 6 −14 −2 9 70 72 6 −12 −2 9 158 160 5 −10 −2 9 141 139 4 −8 −2 9 143 142 11 −6 −2 9 457 429 24 −4 −2 9 451 452 24 −2 −2 9 210 222 9 0 −2 9 64 60 5 2 −2 9 162 166 7 4 −2 9 136 145 7 6 −2 9 555 517 21 8 −2 9 215 235 9 10 −2 9 134 140 6 12 −2 9 60 61 6 −25 −1 9 118 108 9 −23 −1 9 130 122 26 −21 −1 9 191 179 17 −19 −1 9 251 243 9 −17 −1 9 92 87 11 −15 −1 9 205 206 6 −13 −1 9 251 270 7 −11 −1 9 423 395 22 −9 −1 9 442 401 24 −7 −1 9 322 303 18 −5 −1 9 445 414 21 −3 −1 9 474 459 28 −1 −1 9 85 90 10 1 −1 9 347 342 11 3 −1 9 188 196 6 5 −1 9 159 168 8 7 −1 9 91 83 6 9 −1 9 46 63 10 11 −1 9 63 77 7 13 −1 9 42 44 10 15 −1 9 0 16 1 −26 0 9 3 29 3 −24 0 9 0 13 1 −22 0 9 41 69 25 −20 0 9 125 141 10 −18 0 9 54 58 13 −16 0 9 388 370 13 −14 0 9 308 276 17 −12 0 9 527 542 27 −10 0 9 356 376 19 −8 0 9 937 380 48 −6 0 9 348 375 18 −4 0 9 0 21 1 −2 0 9 115 141 9 0 0 9 176 201 11 2 0 9 360 363 12 4 0 9 89 84 4 6 0 9 230 235 6 8 0 9 0 13 1 10 0 9 87 92 5 12 0 9 73 75 7 14 0 9 40 38 12 −27 1 9 45 37 17 −25 1 9 118 108 10 −23 1 9 132 121 10 −21 1 9 197 178 12 −19 1 9 259 244 14 −17 1 9 78 89 13 −15 1 9 193 205 13 −11 1 9 415 395 22 −9 1 9 458 401 23 −7 1 9 352 303 17 −5 1 9 404 414 23 −3 1 9 550 460 24 −1 1 9 100 90 12 1 1 9 363 341 12 3 1 9 194 197 6 5 1 9 162 169 6 7 1 9 96 94 6 9 1 9 67 63 10 11 1 9 88 77 12 13 1 9 43 43 16 −26 2 9 49 30 16 −24 2 9 56 50 17 −22 2 9 0 30 1 −20 2 9 227 225 13 −6 2 9 455 429 24 −4 2 9 462 453 24 −2 2 9 236 220 12 0 2 9 80 61 9 2 2 9 160 167 6 4 2 9 147 146 5 −21 −3 12 99 93 5 −19 −3 12 95 112 5 −17 −3 12 53 61 6 −15 −3 12 0 12 1 −13 −3 12 113 114 5 −11 −3 12 33 36 12 −9 −3 12 158 150 9 −7 −3 12 190 172 9 −5 −3 12 61 51 7 −3 −3 12 153 142 6 −1 −3 12 105 96 5 1 −3 12 148 143 11 −26 −2 12 64 45 11 −24 −2 12 37 34 14 −22 −2 12 35 41 15 −20 −2 12 57 78 9 −18 −2 12 143 182 11 −16 −2 12 225 218 7 −14 −2 12 263 256 8 −12 −2 12 98 109 4 −10 −2 12 70 59 5 −8 −2 12 131 135 4 −6 −2 12 238 238 6 −4 −2 12 220 243 14 −2 −2 12 140 134 7 0 −2 12 76 71 6 2 −2 12 277 294 11 4 −2 12 103 112 7 6 −2 12 202 209 8 8 −2 12 99 87 6 −25 −1 12 50 40 12 −23 −1 12 112 98 17 −21 −1 12 138 159 16 −19 −1 12 133 123 15 −17 −1 12 95 101 5 −15 −1 12 69 76 8 −13 −1 12 340 351 9 −11 −1 12 178 197 5 −9 −1 12 164 172 5 −7 −1 12 191 218 6 −5 −1 12 62 64 6 −3 −1 12 249 240 7 −1 −1 12 199 193 6 1 −1 12 151 146 7 3 −1 12 117 105 7 5 −1 12 62 75 7 7 −1 12 74 79 7 9 −1 12 51 54 9 11 −1 12 31 35 13 −26 0 12 41 31 28 −24 0 12 127 191 10 −22 0 12 62 67 23 −20 0 12 174 152 9 −18 0 12 0 20 1 −16 0 12 138 148 6 −14 0 12 12 8 11 −12 0 12 92 108 6 −10 0 12 28 29 27 −8 0 12 176 193 7 −6 0 12 280 290 8 −4 0 12 109 115 3 −2 0 12 24 4 20 0 0 12 269 271 7 2 0 12 0 14 1 4 0 12 51 61 6 6 0 12 76 70 5 8 0 12 0 23 1 10 0 12 155 143 8 12 0 12 36 39 11 −27 1 12 45 41 18 −25 1 12 53 39 18 −23 1 12 98 98 11 −21 1 12 122 123 6 −19 1 12 95 100 10 −17 1 12 73 77 12 −15 1 12 330 351 17 −11 1 12 184 198 7 −9 1 12 173 171 6 −7 1 12 196 217 6 −5 1 12 58 65 8 −3 1 12 236 239 7 −1 1 12 182 192 7 1 1 12 142 145 8 3 1 12 111 106 9 5 1 12 72 75 7 7 1 12 80 79 8 9 1 12 41 54 16 −18 0 15 0 19 1 −16 0 15 75 77 9 −14 0 15 252 244 9 −12 0 15 68 41 8 −10 0 15 52 39 18 −8 0 15 278 270 10 −6 0 15 309 278 8 −4 0 15 122 129 4 −2 0 15 99 106 6 0 0 15 39 36 16 2 0 15 146 144 8 4 0 15 19 10 19 6 0 15 52 43 9 −25 1 15 33 33 33 −23 1 15 63 48 13 −21 1 15 110 111 9 −19 1 15 0 16 1 −17 1 15 139 149 9 −15 1 15 167 158 16 −13 1 15 122 129 7 −11 1 15 376 357 13 −9 1 15 261 241 10 −7 1 15 335 315 11 −5 1 15 116 121 6 −3 1 15 187 199 8 −1 1 15 53 56 9 1 1 15 183 163 9 3 1 15 47 51 20 −18 2 15 45 56 24 −16 2 15 185 181 12 −14 2 15 206 189 13 −12 2 15 131 132 10 −10 2 15 121 122 7 −8 2 15 124 125 7 −6 2 15 265 273 13 −4 2 15 189 195 18 −2 2 15 177 188 11 0 2 15 118 126 14 2 2 15 60 61 7 4 2 15 51 39 8 6 2 15 59 56 9 −13 3 15 151 155 13 −11 3 15 301 272 15 −9 3 15 133 116 9 −7 3 15 131 127 9 −5 3 15 71 78 8 −3 3 15 36 28 17 −1 3 15 70 79 15 1 3 15 105 96 6 3 3 15 27 16 21 −8 4 15 140 143 9 −6 4 15 94 92 9 −4 4 15 54 42 13 −2 4 15 0 6 1 0 4 15 53 48 9 −11 −5 16 100 98 7 −18 −4 16 103 94 9 −16 −4 16 77 66 6 −14 −4 16 196 164 7 −12 −4 16 64 61 7 −10 −4 16 32 27 14 −8 −4 16 19 25 19 −6 −4 16 16 22 16 −4 −4 16 17 30 17 −2 −4 16 38 59 21 −23 −3 16 41 36 12 −21 −3 16 21 17 21 −19 −3 16 0 16 1 −17 −3 16 39 48 10 −15 −3 16 40 51 13 −13 −3 16 173 174 16 −11 −3 16 48 41 10 −9 −3 16 65 68 7 −7 −3 16 72 83 6 −5 −3 16 116 117 5 −24 −2 16 47 44 9 −22 −2 16 29 46 28 −20 −2 16 31 36 20 −18 −2 16 85 95 8 −16 −2 16 206 188 8 −14 −2 16 202 188 6 −12 −2 16 221 194 6 −10 −2 16 347 339 10 −8 −2 16 77 78 7 −6 −2 16 88 98 7 −4 −2 16 15 20 14 −2 −2 16 56 63 8 −16 0 19 22 24 22 −14 0 19 12 10 11 −12 0 19 58 68 9 −10 0 19 16 39 15 −8 0 19 143 138 6 −6 0 19 69 61 9 −4 0 19 19 24 19 −2 0 19 38 37 13 0 0 19 94 76 6 −23 1 19 133 114 9 −21 1 19 45 38 19 −19 1 19 118 122 8 −17 1 19 92 104 14 −15 1 19 38 27 16 −13 1 19 31 58 27 −11 1 19 48 68 12 −9 1 19 114 118 9 −7 1 19 0 23 1 −5 1 19 63 57 8 −3 1 19 33 35 33 −22 2 19 56 37 13 −20 2 19 36 49 36 −18 2 19 78 64 11 −16 2 19 31 48 31 −14 2 19 40 44 19 −12 2 19 0 20 1 −10 2 19 62 63 9 −8 2 19 60 61 9 −6 2 19 39 52 14 −4 2 19 85 76 10 −2 2 19 67 64 10 −17 3 19 79 84 10 −15 3 19 51 45 17 −13 3 19 0 24 1 −11 3 19 25 27 24 −9 3 19 113 105 6 −7 3 19 75 66 7 −5 3 19 53 53 8 −15 −3 20 30 17 30 −13 −3 20 92 84 6 −11 −3 20 0 5 1 −9 −3 20 31 30 11 −20 −2 20 59 60 7 −18 −2 20 16 43 16 −16 −2 20 59 39 9 −14 −2 20 59 54 10 −12 −2 20 0 8 1 −10 −2 20 62 49 9 −8 −2 20 59 55 8 −6 −2 20 22 16 22 −23 −1 20 10 29 9 −21 −1 20 66 47 7 −19 −1 20 47 27 20 −17 −1 20 0 14 1 −15 −1 20 80 78 6 −13 −1 20 47 56 9 −11 −1 20 62 70 10 −9 −1 20 91 89 7 −7 −1 20 119 108 7 −5 −1 20 53 34 9 −3 −1 20 74 74 6 −22 0 20 34 27 17 −20 0 20 143 124 7 −18 0 20 27 39 26 −16 0 20 48 46 11 −14 0 20 29 31 28 −12 0 20 171 156 8 −10 0 20 171 143 7 −16 −2 2 0 32 1 −14 −2 2 233 232 6 −12 −2 2 417 450 9 −10 −2 2 873 787 45 −8 −2 2 97 113 9 −6 −2 2 690 741 38 −4 −2 2 151 161 12 −2 −2 2 184 215 12 0 −2 2 494 462 14 2 −2 2 488 531 30 10 −2 2 137 128 5 12 −2 2 218 213 10 14 −2 2 83 96 7 16 −2 2 87 108 7 18 −2 2 155 147 8 20 −2 2 31 49 15 −23 −1 2 79 62 7 −21 −1 2 28 35 27 −19 −1 2 111 113 6 −17 −1 2 69 63 9 −15 −1 2 121 117 5 −13 −1 2 172 172 7 −11 −1 2 375 405 22 −9 −1 2 203 198 12 −7 −1 2 933 965 48 −5 −1 2 697 678 25 −3 −1 2 422 411 14 −1 −1 2 666 618 23 3 −1 2 44 56 5 5 −1 2 373 413 20 7 −1 2 173 197 10 9 −1 2 328 317 17 11 −1 2 235 244 6 13 −1 2 155 154 6 15 −1 2 110 111 7 17 −1 2 107 94 8 19 −1 2 50 56 11 21 −1 2 114 100 7 −22 0 2 36 38 35 −20 0 2 78 80 11 −18 0 2 92 105 11 −16 0 2 0 4 1 −14 0 2 152 146 8 −12 0 2 118 127 11 −10 0 2 434 460 22 −8 0 2 831 815 42 −6 0 2 32 40 32 −4 0 2 909 875 46 −2 0 2 99 107 4 0 0 2 265 250 7 2 0 2 354 339 18 4 0 2 437 497 22 6 0 2 116 136 3 8 0 2 196 274 11 10 0 2 57 52 15 12 0 2 134 145 5 14 0 2 78 74 7 16 0 2 43 63 13 18 0 2 38 41 22 −23 1 2 44 62 14 −21 1 2 50 35 16 −19 1 2 95 113 11 −17 1 2 64 63 17 −15 1 2 122 116 9 −13 1 2 167 171 7 −11 1 2 417 405 20 −9 1 2 224 198 11 −7 1 2 941 964 48 −5 1 2 713 680 25 −3 1 2 401 410 15 −1 1 2 628 621 35 1 1 2 1352 1283 69 3 1 2 45 52 13 5 1 2 392 413 19 7 1 2 183 195 10 9 1 2 333 319 17 11 1 2 239 244 9 13 1 2 155 153 8 15 1 2 89 111 10 17 1 2 94 93 10 −22 2 2 44 43 23 −20 2 2 27 33 27 −18 2 2 57 90 20 −16 2 2 0 32 1 −14 2 2 237 232 13 −12 2 2 394 428 21 −8 2 2 129 115 9 −1 1 4 720 680 35 1 1 4 467 409 23 3 1 4 480 520 28 5 1 4 218 222 13 7 1 4 239 241 13 9 1 4 74 76 8 11 1 4 148 148 7 13 1 4 236 216 12 15 1 4 181 146 6 −24 2 4 30 23 29 −22 2 4 0 31 1 −20 2 4 229 215 13 −18 2 4 299 273 15 −16 2 4 167 178 11 −14 2 4 153 171 10 −4 2 4 130 119 8 −2 2 4 263 261 14 0 2 4 213 193 12 2 2 4 231 220 13 4 2 4 587 541 30 6 2 4 310 288 17 8 2 4 116 99 6 10 2 4 50 42 15 12 2 4 88 85 11 18 2 4 66 64 11 −23 3 4 30 34 29 −21 3 4 44 59 29 −19 3 4 41 22 41 −17 3 4 153 169 11 15 3 4 86 97 12 17 3 4 46 52 19 10 4 4 84 95 11 12 4 4 22 30 21 14 4 4 34 14 34 16 4 4 31 11 31 −14 −6 5 11 27 10 −12 −6 5 74 75 11 −10 −6 5 30 18 13 −8 −6 5 105 99 5 −6 −6 5 38 36 9 −4 −6 5 134 160 7 −2 −6 5 117 110 4 0 −6 5 32 27 22 2 −6 5 71 59 9 4 −6 5 92 84 8 6 −6 5 64 54 9 −17 −6 5 14 8 13 −15 −5 5 0 25 1 −13 −5 5 66 67 7 −11 −5 5 160 156 5 −9 −5 5 266 255 8 −7 −5 5 279 256 8 −5 −5 5 190 189 5 −3 −5 5 123 125 5 −1 −5 5 77 78 5 1 −5 5 166 163 10 3 −5 5 61 64 11 5 −5 5 30 40 30 7 −5 5 92 97 9 9 −5 5 60 45 13 11 −5 5 24 28 23 −20 −4 5 28 13 20 −18 −4 5 20 21 20 −16 −4 5 54 65 9 −14 −4 5 218 247 6 −12 −4 5 182 10 6 −10 −4 5 219 206 6 −8 −4 5 113 103 3 −6 −4 5 127 113 5 −4 −4 5 178 181 5 −2 −4 5 116 107 4 0 −4 5 125 102 5 2 −4 5 112 103 19 4 −4 5 57 66 12 6 −4 5 157 157 11 8 −4 5 71 80 12 10 −4 5 43 47 24 12 −4 5 54 42 17 14 −4 5 29 24 23 −23 −3 5 51 50 7 −21 −3 5 57 65 8 −19 −3 5 190 191 8 −17 −3 5 206 193 6 −15 −3 5 38 39 11 −13 −3 5 196 206 6 −11 −3 5 118 119 4 −9 −3 5 246 250 5 −9 −3 7 313 303 6 −7 −3 7 92 80 3 −5 −3 7 255 251 7 −3 −3 7 201 201 8 −1 −3 7 141 143 7 1 −3 7 177 166 8 3 −3 7 225 233 12 5 −3 7 149 132 9 7 −3 7 233 226 13 9 −3 7 69 58 14 −24 −2 7 30 33 29 −22 −2 7 70 48 12 −20 −2 7 143 127 7 −18 −2 7 65 57 10 −16 −2 7 180 182 6 −14 −2 7 154 167 5 −12 −2 7 140 141 4 −10 −2 7 266 246 15 −8 −2 7 152 150 10 −6 −2 7 242 252 15 −4 −2 7 225 294 13 −2 −2 7 208 193 12 0 −2 7 160 160 12 4 −2 7 80 83 5 6 −2 7 204 207 8 8 −2 7 0 15 1 10 −2 7 193 210 8 12 −2 7 60 74 6 14 −2 7 130 119 7 16 −2 7 55 58 5 −25 −1 7 73 65 9 −23 −1 7 35 82 35 −21 −1 7 104 108 14 −19 −1 7 258 252 10 −17 −1 7 154 157 6 −15 −1 7 388 397 11 −13 −1 7 157 152 10 −11 −1 7 360 291 19 −9 −1 7 814 760 43 −7 −1 7 783 724 40 −5 −1 7 915 845 48 −3 −1 7 102 115 7 −1 −1 7 218 207 8 1 −1 7 0 28 1 3 −1 7 500 522 29 5 −1 7 475 492 13 7 −1 7 285 276 9 9 −1 7 142 142 8 11 −1 7 271 269 13 13 −1 7 36 21 14 15 −1 7 55 51 8 17 −1 7 0 31 1 −26 0 7 29 41 29 −24 0 7 0 5 1 −22 0 7 63 72 13 −20 0 7 45 52 22 −18 0 7 98 94 11 −16 0 7 55 82 14 −14 0 7 159 160 12 −12 0 7 274 228 15 −10 0 7 312 305 17 −8 0 7 176 158 7 −6 0 7 263 307 15 −4 0 7 750 803 34 −2 0 7 750 790 27 0 0 7 805 867 41 2 0 7 451 519 23 4 0 7 88 81 11 6 0 7 156 153 5 8 0 7 193 174 6 10 0 7 360 348 9 12 0 7 70 65 6 14 0 7 0 18 1 16 0 7 9 45 8 −25 1 7 59 66 15 −23 1 7 63 62 14 −21 1 7 114 108 10 −19 1 7 277 253 13 −17 1 7 154 156 10 −15 1 7 375 397 19 −9 1 7 831 760 42 −7 1 7 788 722 40 −5 1 7 944 844 47 −3 1 7 119 116 9 −1 1 7 223 207 12 1 1 7 0 26 1 3 1 7 566 522 26 6 2 9 521 517 18 8 2 9 220 236 13 10 2 9 126 140 6 12 2 9 62 60 18 14 2 9 0 23 1 −3 3 9 98 113 10 −1 3 9 357 362 19 1 3 9 308 293 15 3 3 9 368 363 18 5 3 9 211 206 8 7 3 9 82 79 7 9 3 9 59 64 17 11 3 9 69 50 8 13 3 9 76 69 6 2 4 9 139 142 10 4 4 9 94 95 10 6 4 9 0 20 1 8 4 9 92 73 9 10 4 9 64 55 8 7 5 9 31 29 30 −8 −6 10 128 126 6 −6 −6 10 24 22 24 −4 −6 10 56 57 10 −2 −6 10 34 50 20 0 −6 10 0 13 1 −17 −5 10 0 37 1 −15 −5 10 59 72 9 −13 −5 10 37 46 36 −11 −5 10 52 45 9 −9 −5 10 90 83 6 −7 −5 10 80 68 9 −5 −5 10 51 59 30 −3 −5 10 0 25 1 −1 −5 10 115 137 8 1 −5 10 157 159 10 3 −5 10 126 132 9 5 −5 10 86 101 8 −22 −4 10 46 43 10 −20 −4 10 71 63 7 −18 −4 10 93 97 6 −16 −4 10 83 79 6 −14 −4 10 110 111 4 −12 −4 10 198 196 6 −10 −4 10 133 130 13 −8 −4 10 17 20 17 −6 −4 10 68 71 6 −4 −4 10 51 37 11 −2 −4 10 306 330 15 0 −4 10 134 141 9 2 −4 10 175 172 11 4 −4 10 52 45 16 6 −4 10 18 44 18 8 −4 10 68 77 11 −23 −3 10 139 120 13 −21 −3 10 102 93 10 −19 −3 10 191 189 9 −17 −3 10 52 54 9 −15 −3 10 262 295 8 −13 −3 10 268 257 6 −11 −3 10 30 34 10 −9 −3 10 85 77 9 −7 −3 10 132 145 5 −5 −3 10 182 173 8 −3 −3 10 165 162 7 −1 −3 10 105 96 11 1 −3 10 257 238 13 3 −3 10 369 376 18 −26 −2 10 73 68 11 −24 −2 10 75 56 7 −22 −2 10 53 44 9 −20 −2 10 20 22 19 −18 −2 10 35 37 16 −16 −2 10 41 61 13 −14 −2 10 162 157 6 −12 −2 10 256 247 6 −10 −2 10 116 102 8 −8 −2 10 299 288 7 −6 −2 10 256 249 7 −4 −2 10 143 144 7 −2 −2 10 92 81 6 0 −2 10 164 172 8 2 −2 10 152 157 7 4 −2 10 108 110 7 6 −2 10 59 61 6 8 −2 10 28 34 16 10 −2 10 116 104 6 12 −2 10 23 26 16 −14 2 12 42 34 25 −12 2 12 91 108 10 −10 2 12 67 58 12 −8 2 12 119 135 9 −6 2 12 243 238 13 −4 2 12 230 244 10 −2 2 12 138 135 12 0 2 12 73 71 8 2 2 12 273 294 20 4 2 12 109 112 10 6 2 12 195 209 8 8 2 12 89 86 6 10 2 12 63 58 6 −9 3 12 142 150 11 −7 3 12 163 172 13 −5 3 12 57 51 16 −3 3 12 149 142 12 −1 3 12 112 98 9 1 3 12 130 143 7 3 3 12 75 74 9 5 3 12 120 126 11 7 3 12 79 70 7 9 3 12 65 66 6 −4 4 12 76 66 11 −2 4 12 63 58 13 0 4 12 94 89 10 2 4 12 85 83 9 4 4 12 60 48 11 6 4 12 38 29 18 −17 −5 13 60 55 10 −15 −5 13 134 118 12 −13 −5 13 102 78 11 −11 −5 13 87 68 6 −9 −5 13 112 94 5 −7 −5 13 132 117 10 −5 −5 13 80 78 9 −3 −5 13 57 52 11 −1 −5 13 58 56 10 1 −5 13 56 61 10 −20 −4 13 94 82 11 −18 −4 13 27 50 27 −16 −4 13 43 44 12 −14 −4 13 172 160 20 −12 −4 13 125 134 6 −10 −4 13 196 222 12 −8 −4 13 114 130 6 −6 −4 13 108 116 5 −4 −4 13 39 41 27 −2 −4 13 56 55 14 0 −4 13 82 85 10 2 −4 13 80 70 10 −23 −3 13 55 39 7 −21 −3 13 148 131 6 −19 −3 13 118 134 6 −17 −3 13 52 59 8 −15 −3 13 43 59 9 −13 −3 13 60 73 9 −11 −3 13 117 110 7 −9 −3 13 80 81 7 −7 −3 13 296 280 21 −5 −3 13 178 199 24 −3 −3 13 158 160 10 −26 −2 13 93 70 6 −24 −2 13 38 35 13 −22 −2 13 42 52 10 −20 −2 13 121 137 5 −18 −2 13 111 137 5 −16 −2 13 190 178 7 −14 −2 13 87 87 6 −12 −2 13 310 283 7 −10 −2 13 154 143 4 −8 −2 13 119 124 5 −6 −2 13 240 232 8 −4 −2 13 117 122 7 −2 −2 13 197 186 9 0 −2 13 79 84 6 2 −2 13 41 54 9 4 −2 13 36 46 11 6 −2 13 153 146 7 −27 −1 13 43 55 17 −25 −1 13 92 82 7 −23 −1 13 95 89 8 −21 −1 13 83 91 6 −19 −1 13 126 124 6 −17 −1 13 257 248 7 −15 −1 13 181 190 6 −13 −1 13 39 40 24 0 −2 16 0 15 1 2 −2 16 83 67 6 −25 −1 16 101 85 5 −23 −1 16 63 52 7 −21 −1 16 80 75 8 −19 −1 16 50 48 9 −17 −1 16 135 152 5 −15 −1 16 314 331 9 −13 −1 16 258 272 13 −11 −1 16 243 237 11 −9 −1 16 312 151 8 −7 −1 16 174 213 6 −5 −1 16 219 16 7 −3 −1 16 29 16 28 −1 −1 16 161 153 8 1 −1 16 65 68 8 3 −1 16 57 55 8 5 −1 16 52 40 7 −26 0 16 70 48 7 −24 0 16 34 7 25 −22 0 16 112 109 14 −20 0 16 51 60 9 −18 0 16 160 183 11 −16 0 16 81 100 9 −14 0 16 534 561 34 −12 0 16 98 86 6 −10 0 16 363 337 12 −8 0 16 102 102 12 −6 0 16 144 149 7 −4 0 16 12 21 11 −2 0 16 123 132 7 0 0 16 9 35 8 2 0 16 96 93 7 4 0 16 94 78 6 6 0 16 26 14 25 −23 1 16 74 51 11 −21 1 16 95 75 10 −19 1 16 36 49 36 −17 1 16 151 153 11 −15 1 16 322 236 11 −13 1 16 262 270 12 −11 1 16 225 236 14 −9 1 16 309 299 16 −7 1 16 164 152 13 −5 1 16 176 212 9 −3 1 16 20 14 19 −1 1 16 159 153 18 1 1 16 77 68 6 3 1 16 58 56 11 5 1 16 26 40 23 −20 2 16 13 36 13 −18 2 16 80 94 11 −16 2 16 208 189 12 −14 2 16 192 190 13 −12 2 16 221 193 13 −10 2 16 339 338 17 −8 2 16 81 79 8 −6 2 16 94 98 17 −4 2 16 10 21 10 −2 2 16 48 63 9 0 2 16 28 15 28 2 2 16 88 67 5 4 2 16 0 23 1 −15 3 16 0 51 1 −13 3 16 187 174 11 −11 3 16 67 40 15 −9 3 16 63 69 14 −7 3 16 63 83 12 −5 3 16 109 118 6 −3 3 16 88 99 6 −1 3 16 77 77 7 1 3 16 60 53 7 −8 4 16 0 25 1 −6 4 16 0 22 1 −4 4 16 28 29 27 −2 4 16 61 60 9 −18 −4 16 20 32 19 −16 −4 17 64 67 6 −14 −4 17 62 61 7 −12 −4 17 156 141 6 −10 −4 17 43 48 8 −8 −4 17 59 52 13 −6 −4 17 50 52 14 −21 −3 17 0 15 1 −19 −3 17 51 60 10 −17 −3 17 75 74 7 −15 −3 17 84 83 6 −8 0 20 14 22 13 −6 0 20 49 29 11 −4 0 20 62 45 8 −23 1 20 50 29 14 −21 1 20 42 46 21 −19 1 20 34 27 21 −17 1 20 0 14 1 −15 1 20 65 78 8 −13 1 20 55 56 10 −11 1 20 82 70 11 −9 1 20 91 88 6 −7 1 20 116 109 6 −5 1 20 32 34 32 −20 2 20 72 60 9 −18 2 20 0 43 1 −16 2 20 0 39 1 −14 2 20 66 53 9 −12 2 20 0 7 1 −10 2 20 55 48 10 −8 2 20 41 56 13 −6 2 20 0 15 1 −15 3 20 12 16 11 −13 3 20 82 85 9 −11 3 20 0 6 1 −9 3 20 0 29 1 −16 −2 21 44 38 12 −14 −2 21 53 19 9 −12 −2 21 48 25 11 −10 −2 21 17 4 17 −8 −2 21 26 23 26 −21 −1 21 35 32 20 −19 −1 21 38 45 20 −17 −1 21 79 59 9 −15 −1 21 91 75 7 −13 −1 21 44 53 14 −11 −1 21 64 71 9 −9 −1 21 43 31 12 −7 −1 21 40 35 12 −22 0 21 26 4 25 −20 0 21 26 10 25 −18 0 21 0 1 1 −16 0 21 91 72 6 −14 0 21 41 46 12 −12 0 21 104 87 6 −8 0 21 20 16 20 −6 0 21 36 9 14 −21 1 21 44 33 16 −19 1 21 36 46 20 −17 1 21 67 59 7 −15 1 21 78 75 6 −13 1 21 50 54 10 −11 1 21 68 71 7 −9 1 21 44 30 10 −7 1 21 27 35 27 −18 2 21 27 32 26 −16 2 21 36 37 18 −14 2 21 0 18 1 −12 2 21 23 25 23 −10 2 21 0 4 1 −8 2 21 6 23 6 −18 0 22 16 31 16 −16 0 22 40 40 40 −14 0 22 29 7 28 −17 1 22 33 31 14 −15 1 22 68 34 10 −13 1 22 86 76 6 −11 1 22 68 71 8

REFERENCES

-   1. CrysAlis RED, Oxford Diffraction Ltd., Version 1.171.28 cycle2     beta (release 25-10-2005 CrysAlis171.NET) (compiled Oct. 25 2005,     08:50:05). Empirical absorption correction using spherical     harmonics, implemented in SCALE3 ABSPACK scaling algorithm. -   2. CrysAlis CCD, Oxford Diffraction Ltd., Version 1.171.28 cycle2     beta; CrysAlis RED, Oxford Diffraction Ltd., Version 1.171.28 cycle2     beta. -   3. G. M. Sheidrick, Acta Crystallogr. 1990, A46, 467-473. -   4. G. M. Sheldrick, SHELXL93. Program for the Reminement of Crystal     Structures, Univ. of Götttingen, Germany. -   5. International Tables for Crystallography, Ed. A. J. C. Wilson,     Kluwer:Dordrecth, 1992, Vol. C.

Example 2 Synthesis of 24F2-DM

The preparation of 24F2-DM having the basic structure I can be accomplished by a common general method otherwise referred to as the condensation of a bicyclic Windaus-Grundmann type ketone II with the allylic phosphine oxide III to the corresponding 19-nor-vitamin D analog IV followed by deprotection at C-1 and C-3 in the latter compound IV to obtain compound I (24F2-DM).

In phosphine oxide III, Y₁ and Y₂ are preferably hydroxy-protecting groups such as silyl protecting groups. The t-butyldimethylsilyl (TMDMS) group is an example of a particularly useful hydroxy-protecting group. The process described above represents an application of the convergent synthesis concept, which has been applied effectively to the preparation of numerous vitamin D compounds (see Lythgoe et al., J. Chem. Soc. Perkin Trans. 1, 590 (1978); Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Toh et al., J. Org. Chem. 48, 1414 (1983); Baggiolini et al., J. Org. Chem. 51, 3098 (1986); Sardina et al., J. Org. Chem. 51, 1264 (1986); J. Org. Chem. 51, 1269 (1986); DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca et al., U.S. Pat. No. 5,536,713; and DeLuca et al., U.S. Pat. No. 5,843,928 all of which are hereby incorporated by reference in their entirety and for all purposes as if fully set forth herein.

Phosphine oxide III is a convenient reagent that can be used to prepare a large number of 19-nor-vitamin D compounds and is prepared according to the procedures described by Sicinski et al., J. Med. Chem., 41, 4662 (1998), DeLuca et al., U.S. Pat. No. 5,843,928; Perlman et al., Tetrahedron Lett. 32, 7663 (1991); and DeLuca et al., U.S. Pat. No. 5,086,191 which are hereby incorporated by reference in their entirety as if fully set forth herein.

An overall process for the synthesis of compound I is illustrated and described more completely in U.S. Pat. No. 5,843,928 entitled “2-Alkylidene-19-Nor-Vitamin D Compounds,” the specification of which is specifically incorporated herein by reference. 

We claim:
 1. A compound having the formula

in crystalline form, and named (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D₃, wherein the crystalline form has a molecular packing arrangement defined by space group C2 and unit cell dimensions a=23.88 Å, b=6.16 Å, c=19.63 Å, α=90°, β=121.83° and γ=90°.
 2. A three dimensional structure for (20R)-9-nor-24-diafluoro-1α,25-dihydroxyvitamin D as defined by the molecular packing arrangement set forth in claim
 1. 3. A method of purifying (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D₃, comprising the steps of: (a) preparing a solvent comprising hexane; (b) adding a product containing (20R)-9-nor-24-difluoro-1α,25-dihydroxyvitamin D₃ to be purified to said hexane to form a suspension of the product in the hexane; (c) adding 2-propanol dropwise to the suspension to form a mixture of the product in the hexane and 2-propanol; (d) heating the mixture to dissolve the product containing (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D- to be purified in said mixture; (e) cooling said mixture and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D crystals; and (f) separating the (20R)-19-nor-24-difluoro-1α,25-dihydroxyvitamin D₃ crystals from the solvent.
 4. The method of claim 3 including the further step of allowing said solvent and dissolved product to cool to ambient temperature prior to cooling below ambient temperature.
 5. The method of claim 3 wherein the step of separating comprises filtering the mixture and precipitate to obtain the crystals.
 6. The method of claim 3 including, a further step (g) comprising repeating steps (a) through (f) using the recovered crystals from step (f) as the product of step (b).
 7. The method of claim 3 wherein said mixture comprises about 15% 2-propanol and about 85% hexane by volume. 